Ras inhibitors and uses thereof

Abstract

The present disclosure relates to novel Ras inhibitors, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of diseases and / or conditions.

Description

Attorney Ref: 41827-65010 (044WO)RAS INHIBITORS AND USES THEREOF1. BACKGROUND

[0001] Belonging to the family of GTPases, Ras (rat sarcoma virus) proteins are involved in cell signaling and proliferation pathways. While these types of Ras-dependent pathways are normally strictly regulated, mutations in Ras proteins are known to be highly disruptive, contributing to the promotion of numerous diseases.

[0002] Because the Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in various human cancers, these proteins have become targets for anticancer treatment. Ras proteins, when mutated, contribute to an estimated 30% of all human cancers in the United States — a substantial portion of which have fatal outcomes. Most oncogenic mutations in these proteins occur at hotspot codons 12, 13, or 61. Factors such as activating mutations, overexpression or upstream activation often disrupt the regulation of Ras proteins in human tumors. In addition, Ras is commonly associated with human cancer due to frequently found activating mutations. For instance, such mutations at codon 12 skew the balance of Ras mutant proteins significantly towards the “on” state — Ras(ON) — by suppressing both GTPase-activating protein (GAP) -dependent and intrinsic hydrolysis rates of GTP. This leads to an upsurge in oncogenic MAPK signaling. Furthermore, Ras has the unique ability to get activated even in low concentrations of GTP due to its picomolar affinity for it. Lastly, mutations at codons 13 (such as G13C) and 61 (like Q61K) of Ras also account for the oncogenic activity seen in certain types of cancer.

[0003] Ras proteins have traditionally been considered to be undruggable by small molecule inhibitors. One recent advancement in this regard involves the development of the two small molecule KRASG12Cinhibitors sotorasib and adagrasib, which have received FDA approval for the treatment of KRAS G12C-mutated non-small cell lung cancer. However, a major limitation of these drugs is that they function by introducing allele-specific covalent modification to the GDP-bound, inactive state of the Ras protein. Consequently, they display selectivity and efficacy toward only a narrow set of glycine 12C mutated KRAS protein variants, which account for a small percentage of KRAS -mutated cancers. And despite drug discovery efforts targeting Ras during the last several decades, a drug targeting directly Ras is still not approved. Moreover, efforts are also needed for uncovering drugs for cancers driven by the various Ras mutations.

[0004] Accordingly, there remains an unmet medical need for small molecule inhibitors that can suppress oncogenic variants of Ras proteins.2. SUMMARY

[0005] The present disclosure provides compounds, such as Ras inhibitors, in particular macrocyclic Ras inhibitors, compositions comprising the disclosed compounds, and uses thereof.

[0006] In some embodiments, the present disclosure provides Ras inhibitors represented by Formula (I), compositions comprising the disclosed compounds, and uses thereof.Attorney Ref: 41827-65010 (044WO)

[0007] In some embodiments, provided herein is a compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein:- is a single bond or a double bond;R1is H or Ci-Ce alkyl;R2is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)0-6OR2A, -C(O)R2A, -(CH2)0-6CO2R2A-(CH2)0-6OC(O)R2A-NO2, -CN, -N3, -(CH2)0-6N(R2A)(R2B) -(CH2)0-6C(O)N(R2A)(R2B) -(CH2)0-6SR2A, and ring A;ring A is selected from C3-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9- membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C; orR1and R2form, along with the atoms they are attached to, a 5 - to 7- membered heterocycloalkyl substituted with 0, 1, or 2 R2C;each R2Aand R2Bare independently selected from H, Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6OCi-Ce alkyl, -C(O)H, -C(O)Ci-C6alkyl, -(CH2)o6CO2H, -(CH2)o 6CO2Ci-C6alkyl, and C3-C8cycloalkyl; each R2Cis independently selected from Ci-Ce alkyl, halogen, -(CH2)0-6OH, -(CH2)o eOCi-Ce alkyl, oxo,-C(O)H, -C(O)Ci-C6alkyl, -(CH2)0-6CO2H, -(CH2)0-6CO2C1-C6alkyl, -NO2, -N3, -(CH2)o6NH(R2C1), -(CH2)0-6N(R2C1)(R2C2), -(CH2)0-6C(O)N(R2C1)(R2C2), and C3-C8spirocycloalkyl;each R2C1and R2C2are independently H or C1-C6alkyl;X1is NR1Aor C(R1A)i-2, wherein each R1Ais independently H, Ci-Cg alkyl, or Ci-Cg haloalkyl;X2is N or C;R3is ring B, wherein ring B is selected from C4-C8cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, l, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)0-6OC1-C6alkyl, -C(O)H, -C(O)Ci-C6alkyl, and -(CH2)o^C02H; orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4 or 5 heteroatoms selected from N, S, and O, andAttorney Ref: 41827-65010 (044WO) the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6R5ACO3H, - (CH2)1)„CO2CI-C„ alkyl, -(CH2)o 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)o6NHCI-C6alkyl, - (CH2)O^NHR5ACH2OH, -(CH2)O6NHR5ACO2H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6SH, -(CH2)O.6SR5A, -(CH2)O 6SO3H, -(CH2)O 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)0-6NH(CH2)I.4OP(O)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I.6OP(O)(H)(OH), -(CH2)O^P(0)(OH)2, -(CH2)O^P(0)(OC1-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)0^OP(O)(OH)(OCI-C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cn spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Cg alkyl, C4-C8 cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6NH2, -(CH2)0-6N(C1- C6alkyl)2, -(CH2).)„P(O)(OH)2. -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), -(CH2)O^OP(0)(OCI-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)o-eOH, -(CH2)o-eNH2, oxo, C3.s cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O eNHCi-Ce alkyl, oxo, C3-Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2),)., OP(O)(OH)2. -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH:),) „OP(O)(H)(OH). C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;Attorney Ref: 41827-65010 (044WO) each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)O^OP(0)(OH)2, -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), and -(CH2)o6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;each R10, R11, and R12are hydrogen; orR12and X1form, along with the atoms they are attached to, a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl, and the 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 R13; and R10and R11are each hydrogen; andR13is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, and -(CH2)O^P(0)(OCI-C6alkyl)2.

[0008] In some embodiments, the compound of Formula (I) is represented by Formula (I -a):wherein:ring A is selected from Cs-Ce cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl;each R2Cis independently selected from C1-C3 alkyl, halogen, -(CH2)0-6OH, -(CH:),),, OC-C, alkyl, oxo, -C(O)C1-C6alkyl, -(CH2)0-6CO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6NH(R2C1), -(CH2)1-5N(R2C1)(R2C2), -N(R2C1)(R2C2), and -(CH2)0-6C(O)N(R2C1)(R2C2);each R2C1and R2C2are independently H or C1-C3alkyl;R4is H;Attorney Ref: 41827-65010 (044WO) R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 8-membered heterocycloalkyl, and 5- to 9-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;each R5is independently selected from -C2-C6 alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)o 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)0-6NHC1-C6alkyl, -(CH2)O6NHR5ACH2OH, -(CH2)O^NHR5AC02H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6SH, - (CH2)O-6SR5A, -(CH2)O6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)O.6NH(CH2)I.40P(0)(OH)(OCI-C6alkyl), -(CH2)O.6NH(CH2)I.60P(0)(H)(OH), - (CH2)„,. P(O)(OH)2. -(CH2)O^P(0)(OC1-C6alkyl)2, -(CH2)0-6OP(O)(OH)2, -(CH2)0^OP(O)(OH)(OC1- C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), -C4-C8cycloalkyl, -CH2-(C3-C8cycloalkyl), C3-C8fused bicyclic cycloalkyl, -CH2-(C5-C8fused bicyclic cycloalkyl), Ce-Cn spirocyclyl, Ce-Cioaryl, -CH2-(C6-Cioaryl), 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9- membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, -CH2-(7- to 12- membered bicyclic heterocycloalkyl), 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl and -CH2-(5- to 10-membered heteroaryl), wherein each of the -C2-C6alkyl, C4-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; andn is 0, 1, or 2.wherein:R2is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)0-6OR2A, -C(O)R2A, -(CH2)O^C02R2A, -(CH2)0-6OC(O)R2A-NO2, -CN, -Ns, -(CH2)o^N(R2A)(R2B), -(CH2)0-6C(O)N(R2A)(R2B). -(CH2)0-6SR2A, and ring A;ring A is selected from C3-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 8-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C;Attorney Ref: 41827-65010 (044WO) ring B is a 3- to 8-membered heterocycloalkyl; andR5is selected from -C2-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0 6CO2Ci-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0.6NH2, -(CH2)0-6NHC1-C6alkyl, -(CH2)0 6NHR5ACH2OH, -(CH2)0-6NHR5ACO2H, -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)0-6NH(CH2)1-6OP(O)(OH)2, -(CH2)0-6P(O)(OH)2, -(CH2)0-6P(O)(OC1-C6alkyl)2, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -C2-Ce alkyl, C -C’s fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0010] In some embodiments, the compound of Formula (I) is represented by Formula (I-b-1):(I-b-1), wherein:R5is selected from -C2-C6alkyl, -(CH2)0 6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0 6CO2Ci-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)„. NHC G, alkyl, -(CH2)0 6NHR5ACH2OH, -(CH2)0-6NHR5ACO2H, -(CH2)O-6NH(CH2)1.6S03H, -(CH2)O.6NH(CH2)1.6OP(0)(OH)2, -(CH2)O6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9-membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl, and -CH2-(5- to 10-membered heteroaryl), wherein each of the C2-Ce alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0011] In some embodiments, the compound of Formula (I) is represented by Formula (I-b-2):Attorney Ref: 41827-65010 (044WO)wherein:R5is selected from -C1-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, and -(CH2)0-6CO2C1-C6alkyl.

[0012] In some embodiments, the compound of Formula (I) is represented by Formula (I-b-3):(I-b-3),wherein:X1is NCR1A;X2is C; andR5B'and R5B''are independently selected from -C1-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o6CO2Ci-C6alkyl, -(CH2)0.6NH2, and -(CH2)0-6NHC1-C6alkyl.

[0013] In some embodiments, the compound of Formula (I) is represented by Formula (I-c):wherein:Attorney Ref: 41827-65010 (044WO) R6'is selected from H, -C1-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6P(O)(OH)2, -(CH2)0 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;R6''is selected from deuterium, -C1-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)o 6CO2Ci-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)0 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Y is O or NH; andm is 1 or 2.

[0014] In some embodiments, the compound of Formula (I) is represented by Formula (I-d-1):(I-d-1), wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;X1is NR1A, wherein R1Ais selected from H, Ci-Ce alkyl and Ci-Ce haloalkyl;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)0-eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0-6CO2H; or orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Cg alkyl, -(CH2)0 6OH, -(CH2)0 6CO2H, -(CH2)0 6R5ACO2H, - (CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0 6NHCI-C6alkyl, - (CH2)„, NHR CH2OH. -(CH2)O6NHR5ACO2H, -(CH2)O-6NH(CH2)1.6S03H, -(CH2)O.6SH, -(CH2)OAttorney Ref: 41827-65010 (044WO)6SR5A, -(CH2)O 6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O.6NH(CH2)I_6OP(O)(OH)2, -(CH2)O.6NH(CH2)I_4OP(0)(OH)(OCI-C6 alkyl), -(CH2)0.6NH(CH2)I_6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)0^OP(O)(OH)(OCI-C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, C -C’s fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Cg alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0^N(CI- C6alkyl)2, -(CH2)0-6P(O)(OH)2, -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)O^OP(0)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)0-eOH, -(CH2)O-6NH2, OXO, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2Ci-Ce alkyl, -(CH2)0-6NH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)o.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, C6-C10aryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D; andeach R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)„, SO3H. -(CH2)0-6OP(O)(OH)2, -(CH2)06OP(O)(OH)(OCI-C6alkyl), and -(CH2)0 6OP(O)(H)(OH).

[0015] In some embodiments, the compound of Formula (I) is represented by Formula (I-d-2):Attorney Ref: 41827-65010 (044WO)(I-d-2), wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;X1is NR1A, wherein R1Ais selected from H, Ci-Cg alkyl and Ci-Cg haloalkyl;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Cg alkyl, Ci-Cg haloalkyl, halogen, -(CH2)0eOH, -(CH2)0-6OC1-C6alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0-6CO2H; or orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)0-6CO2H, -(CH2)o eR5ACO2H, - (CH2)0^CO2CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0 6NHCI-C6alkyl, - (CH2)„, NHRACH2OH. -(CH2)O6NHR5ACO2H, -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)O.6SH, -(CH2)O-6SR5A, -(CH2)O 6SO3H, -(CH2)O6SO2NH2, -(CH2)O^S02NHCI-C6alkyl, -(CH2)0.6NH(CH2)I_6OP(O)(OH)2, -(CH2)0.6NH(CH2)1-4OP(O)(OH)(OCI-C6alkyl), -(CH2)0-6NH(CH2)1-6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OC1-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, - (CH2)0^OP(O)(OH)(OCI-C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-Attorney Ref: 41827-65010 (044WO)6R5ACO2H, -(CH2), „CO2CI-C„ alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0^N(CI- C6alkyl)2, -(CH2)0-6P(O)(OH)2, -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0^OP(O)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)O-60H, -(CH2)O-6NH2, OXO, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Cg alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)O6CO2Ci-Ce alkyl, -(CH2)0.6NH2, -(CH2)0eNHCi-Ce alkyl, oxo, C3-Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D; andeach R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)06OP(O)(OH)(OCI-C6alkyl), and -(CH2)0 60P(0)(H)(0H).

[0016] In some embodiments, the compound of Formula (I) is represented by Formula (I-e):R11wherein:R1is H;R2is ring A;Attorney Ref: 41827-65010 (044WO) ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)o^C02H; orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Cg alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, - (CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)o.6NH2, -(CH2)0., NHC|-C„ alkyl, - (CH2)O^NHR5ACH2OH, -(CH2)O6NHR5ACO2H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6SH, -(CH2)O-6SR5A, -(CH2)O 6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)O-6NH(CH2)I.40P(0)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I.6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)O^OP(0)(OH)(OCI-C6alkyl), -(CH2)o 6OP(O)(OCi-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6NH2, -(CH2)0-6N(C1- C6alkyl)2, -(CH2)O^P(0)(OH)2, -(CH2)O6P(O)(OC1-C6alkyl)2,-(CH2)o6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)O^OP(0)(OCI-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)o-eOH, -(CH2)o-eNH2, oxo, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)o-eNH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Attorney Ref: 41827-65010 (044WO) C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, Ce-Cn spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)u. CO2H. -(CH2)o 6CO2Ci-C6alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)O^OP(0)(OH)2, -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH2)0^OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;each R5Dis independently selected from -Ci-Cg alkyl, halogen, -(CH2)0-60H, -(CH2)o 6CO2H, -(CH2)o6CO2C1-C6alkyl, -(CH2)o.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), and -(CH2)0 6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;R10and R11are each hydrogen;X3is CH2, N, or O; andR13is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6R5ACO3H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, and -(CH2)O^P(0)(OCI-C6alkyl)2.

[0017] In some embodiments, the compound of Formula (I) is represented by Formula (I-e-1):wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;Attorney Ref: 41827-65010 (044WO) R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)o^C02H; orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Cg alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, - (CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)o.6NH2, -(CH2)0., NHC|-C„ alkyl, - (CH2)0^NHR5ACH2OH, -(CH2)O 6NHR5ACO2H, -(CH2)O-6NH(CH2)I.6S03H, -(CH2)O-6SH, -(CH2)O-6SR5A, -(CH2)O 6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)O-6NH(CH2)I.40P(0)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I.6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)O^OP(0)(OH)(OCI-C6alkyl), -(CH2)o 6OP(O)(OCi-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6NH2, -(CH2)0-6N(C1- C6alkyl)2, -(CH2).)„P(O)(OH)2. -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH2)0^OP(O)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Cg alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)o-eOH, -(CH2)o-eNH2, oxo, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)o-eNH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C;Attorney Ref: 41827-65010 (044WO) each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)u. CO2H. -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)O^OP(0)(OH)2, -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH2)0^OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o6CO2C1-C6alkyl, -(CH2)o.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), and -(CH2)0 6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;R10and R11are each hydrogen;X3is CH2or O; and,R13is deuterium.

[0018] In some embodiments, the compound of Formula (I) is represented by Formula (I-f):wherein:- is a single bond or a double bond;R1is H or Ci-Ce alkyl;R2is selected from Ci-Cg alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)o eOR2A, -C(O)R2A, -(CH2)„ „CO2R2A. -(CH2)0-6OC(O)R2A-NO2, -CN, -N3, -(CH2)0-6N(R2A)(R2B) -(CH2)0-6C(O)N(R2A)(R2B) -(CH2)0-6SR2A, and ring A;Attorney Ref: 41827-65010 (044WO) ring A is selected from C3-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9- membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C; orR1and R2form, along with the atoms they are attached to, a 5 - to 7- membered heterocycloalkyl substituted with 0, 1, or 2 R2C;each R2Aand R2Bare independently selected from H, Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6OCi-Ce alkyl, -C(O)H, -C(O)Ci-C6alkyl, -(CH2)o6CO2H, -(CH2)o 6CO2Ci-C6alkyl, and C3-C8cycloalkyl; each R2Cis independently selected from Ci-Cg alkyl, halogen, -(CH2)0-6OH, -(CH2)o eOCi-Ce alkyl, oxo, -C(O)H, -C(O)Ci-C6alkyl, -(CH2),, CO2H. -(CH2)0^CO2CI-C6alkyl, -NO2, -N3, -(CH2)06NH(R2C1), -(CH2)O^N(R2C1)(R2C2), -(CH2)O 6C(O)N(R2C1)(R2C2), and C3-C8spirocycloalkyl;each R2c1and R2c2are independently H or Ci-Cg alkyl;X1is NR1Aor C(R1A)i-2, wherein each R1Ais independently H, Ci-Cg alkyl, or Ci-Cg haloalkyl;X2is N or C;R6is selected from H, -Ci-C6alkyl, -(CH2)0-6OH, -(CH2)o6CO2H, -(CH2)o6R5ACO2H, -(CH2)o6CO2Ci- C6alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)0-6P(O)(OH)2, -(CH2)o 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;R6is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)u CCfH. -(CH2)u NIV 'COZH. -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, -(CH2)o 6P(O)(OCi-C6alkyl)3, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6- membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Y is O orNH;each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)u CO2H. -(CH2)o 6CO2C1-C6 alkyl, -(CH2)o-eNH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)„.. OP(O)(OH)2. -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH2)0-6OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;Attorney Ref: 41827-65010 (044WO) each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CFhjo 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)O^OP(0)(OH)2, -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), and -(CH2)o6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;each R10, R11, and R12are hydrogen; orR12and X1form, along with the atoms they are attached to, a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl, and the 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 R13; and R10and R11are each hydrogen;R13is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, -(CFFjo 6CO2C1-C6 alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, and -(CH2)O^P(0)(OCI-C6alkyl)2; andm is 1 or 2.

[0019] Also disclosed herein are methods of treatment. The disclosed methods may comprise treating a subject (e.g., a human subject) in need thereof, wherein the subject has a disease, such as cancer. The methods may comprise administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the cancer is a Ras-driven cancer (or mutant-associated cancer). In some embodiments, the Ras-driven cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma, thyroid cancer, cardiac cancer, biliary tract cancer, and hematological cancer.

[0020] In some embodiments, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a compound as disclosed herein (e.g., Formula I) and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.3. DETAILED DESCRIPTION

[0021] When describing the embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated.Attorney Ref: 41827-65010 (044WO)

[0022] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations).Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0023] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0024] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken downAttorney Ref: 41827-65010 (044WO) into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.3.1. Definitions

[0025] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0026] As used herein, the term “acyl” refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality. In some embodiments, it is a Cl -10 acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl. For example, a C4-acyl has three other ring or chain atoms plus carbonyl.

[0027] As used herein, the term “aliphatic” or “aliphatic group” refers to straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic,” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.Attorney Ref: 41827-65010 (044WO)

[0028] As used herein, the term “alkenyl” refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs)-alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0029] As used herein, the term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as Ci-s alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2-propyl, 2 -methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon. When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Cg alkyl” is intended to encompass Ci, C2, C3, C4, C5, Cg, C1.6, C1.5, C1.4, C1.3, C1.2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3.4, C4-6, C4.5, and C5-6 alkyl.

[0030] As used herein, the term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, for example, from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0031] As used herein, the term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0032] As used herein, the term “alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0033] As used herein, the term “alkylene” refers to a divalent alkyl radical. Representative examples of Ci-10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3 -methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.

[0034] As used herein, the term “alkynyl” refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs)-alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, 4-propyl -2 -pentynyl, and 4 butyl 2 hexynyl.Attorney Ref: 41827-65010 (044WO)

[0035] As used herein, the term “aryl” refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system without any heteroatom ring atoms. An aryl group may be selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.

[0036] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0037] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:Attorney Ref: 41827-65010 (044WO)

[0038] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a Ras protein with a compound provided herein includes the administration of a compound provided herein to an individual or patient.

[0039] As used herein, the term “cyano” refers to CN.

[0040] Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl bicyclic (fused, bridged, or spirocyclic) or polycyclic (fused, bridged, or spirocyclic) ring systems are defined based on the nature of the ring system and / or point of attachment. For example, if the entire bicyclic or polycyclic ring system is fully nonaromatic and contains at least one ring heteroatom, then the ring system is a heterocycloalkyl bicyclic or polycyclic ring system. If the entire bicyclic or polycyclic ring system is fully aromatic and contains at least one ring heteroatom, then the ring system is considered a heteroaryl bicyclic or polycyclic ring system. If the bicyclic or polycyclic ring system contains a mix of non-aromatic and aromatic ring systems, then it is the point of attachment that dictates the nature of the ring system: if attached to the non-aromatic cycloalkyl or heterocycloalkyl ring, it is considered a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system; if it is attached to the aromatic aryl or heteroaryl ring, it is considered an aryl or heteroaryl bicyclic or polycyclic ring system.

[0041] As used herein, the term “cycloalkyl” refers to a non-aromatic saturated or unsaturated, monocyclic, bicyclic, or polycyclic ring system containing 3 to 16 ring carbon atoms, but no heteroatom ring atoms. For example, 3-16 carbons, or 3-8 carbons, referred to herein as “(C3-Cs)-cycloalkyl,” derived from a cycloalkane. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8,1Attorney Ref: 41827-65010 (044WO) C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, bicyclo [l.l.l]pentane, norbomane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbomene, and norbomadiene. When cycloalkyl is a saturated monocyclic C3-8cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be substituted with an alcohol (hydroxy), alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic acid, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, ketone, nitro, oxo (a carbonyl on the ring), phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc. In embodiments, the term cycloalkyl is a monocyclic ring. In embodiments, the term “bicyclic cycloalkyl” may refer to a ring system such as a l,l’-bi(cyclohexyl) ring system:. In embodiments, the term “bicyclic cycloalkyl” may refer to a fused ring system such as a decahydronaphthalene ring system:. In embodiments, the term “bicyclic cycloalkyl” may refer to a spirocyclic ring

[0042] As used herein, when the terms “cycloalkyl, bicyclic cycloalkyl, fused bicyclic cycloalkyl, and / or spirocyclyl” (or any combination of the preceding) are used alongside in the same embodiment, the terms are mutually exclusive of each other and not considered subgenera of cycloalkyl. In other words, when used in the same embodiment, the term cycloalkyl refers to a monocyclic ring system whereas a bicyclic or fused cycloalkyl refer to polycyclic ring systems.

[0043] As used herein, the term “halo” or “halogen” refers to -F, -Cl, -Br, and / or -I.

[0044] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogens.Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.Attorney Ref: 41827-65010 (044WO)

[0045] As used herein, the term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or a substituted nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl or N-methyl piperazine)). In embodiments, the heteroatom is selected from oxygen, sulfur, nitrogen, and phosphorus. In another embodiment, the heteroatom is selected from oxygen, sulfur, and nitrogen. In embodiments, the heteroatom is independently oxygen or nitrogen.

[0046] As used herein, the term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. In embodiments, the term “heteroaryl” may be used interchangeably with a divalent aromatic radical. In embodiments, the heteroaryl is a 5-membered heteroaromatic ring. In embodiments, the heteroaryl is a 6-membered heteroaromatic ring. In embodiments, the heteroaryl is a 7-membered heteroaromatic ring. In embodiments, the heteroaryl is a 8-membered heteroaromatic ring. In embodiments, the heteroaryl is a 9-membered heteroaromatic ring. In embodiments, the heteroaryl is a 10-membered heteroaromatic ring. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbozolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydrquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bicyclic, or tricyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” “heteroaromatic,” or “heteroaromatic ring” any of which terms include rings that are optionally substituted. In some embodiments, the heteroaryl is an 8-12 membered bicyclic heteroaryl or a 10-14 membered tricyclic heteroaryl. In embodiments, the term “bicyclic heteroaryl” may refer to a ring system such as a 2-phenylpyridinyl ring system:. In embodiments, the term “bicyclic heteroaryl” may refer to a fused ring system such as an idolyl ring system:Attorney Ref: 41827-65010 (044WO). If the bicyclic or polycyclic ring system contains a mix of non-aromatic and aromatic ring systems, then it is the point of attachment that dictates the nature of the ring system: if attached to the non-aromatic cycloalkyl or heterocycloalkyl ring, it is considered a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system; if it is attached to the aromatic aryl or heteroaryl ring, it is considered an aryl or heteroaryl bicyclic or polycyclic ring system.

[0047] As used herein, when the terms “heteroaryl, bicyclic heteroaryl, and / or fused heteroaryl” (or any combination of the preceding) are used alongside in the same embodiment, the terms are mutually exclusive of each other and not considered subgenera of heteroaryl. In other words, when used in the same embodiment, the term heteroaryl refers to a monocyclic ring system whereas a bicyclic or fused heteroaryl refer to polycyclic ring systems.

[0048] As used herein, a “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” group refers to a ring structure having from 3 to 14 atoms, for example 4 to 13 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of the ring atoms being carbon. In embodiments, the heterocycloalkyl is a 3- to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl is a 4- to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl is a 5 - to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl is a 6- to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl group is a 3 -membered ring. In embodiments, the heterocycloalkyl group is a 4-membered ring. In embodiments, the heterocycloalkyl group is a 5 -membered ring. In embodiments, the heterocycloalkyl group is a 6-membered ring. In embodiments, the heterocycloalkyl group is a 7-membered ring. In embodiments, the heterocycloalkyl group is an 8-membered ring. In embodiments, the heterocycloalkyl group is a 9-membered ring. In embodiments, the heterocycloalkyl group is a 10-membered ring. In embodiments, the heterocycloalkyl group is a 11 -membered ring. In embodiments, the heterocycloalkyl group is a 12-membered ring. In embodiments, the heterocycloalkyl group is a 13-membered ring. In embodiments, the heterocycloalkyl group is a 14-membered ring. The heterocyclyl may be a monocyclic, a bicyclic, a tricyclic, a spirocyclic, or a bridged ring system. The heterocyclic group is independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- \H. H.5H-oxazolo[3, 4-c]oxazolyl, tetrahydro- VH, 3 'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydro- IH-pyrrolizinyl, hexahydro-lH-pyrrolo[2,l- c][ 1,4] oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide,Attorney Ref: 41827-65010 (044WO) tetrahydro- 2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms. In embodiments, the term “bicyclic heterocycloalkyl” may refer to a ring system such as a l-(piperidin-4-yl)piperazinyl ring system:. In embodiments, the term “bicyclic heterocycloalkyl” may refer to a fused ring system such as a 3,4-dihydro-2H- 1 -benzopyran:.00. In embodiments, the term “bicyclic heterocycloalkyl” may refer to a heterospirocyclic ring system such as:. If the bicyclic or polycyclic ring system contains a mix of non-aromatic and aromatic ring systems, then it is the point of attachment that dictates the nature of the ring system: if attached to the non-aromatic cycloalkyl or heterocycloalkyl ring, it is considered a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system; if it is attached to the aromatic aryl or heteroaryl ring, it is considered an aryl or heteroaryl bicyclic or polycyclic ring system.

[0049] As used herein, when the terms “heterocycloalkyl, bicyclic heterocycloalkyl, fused heterocycloalkyl, and / or hetero-spirocyclyl” (or any combination of the preceding) are used alongside in the same embodiment, the terms are mutually exclusive of each other and not considered subgenera of heterocycloalkyl. In other words, when used in the same embodiment, the term heterocycloalkyl refers to a monocyclic ring system whereas a bicyclic or fused heterocycloalkyl refer to polycyclic ring systems.

[0050] As used herein, the term “KRAS” refers to Kirsten rat carcoma virus. The KRAS or “K-Ras” protein is a GTPase, a class of enzymes that convert the nucleotide guanosine triphosphate into guanosine diphosphate. KRAS is an integral part of numerous signal transduction pathways.

[0051] As used herein, the term “lower alkyl” refers to a C1-4straight or branched alkyl group.Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0052] As used herein, the term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0053] As used herein, the term “hydroxy” and “hydroxyl” are used interchangeably and refer to -OH.

[0054] As used herein, the term “oxo” refers to an oxygen that is double bonded to a carbon atom thereby forming a carbonyl.

[0055] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.Attorney Ref: 41827-65010 (044WO)

[0056] A “spirocycle,” “spirocyclyl,” or “spirocyclylene” refers to a chemical entity having two heterocyclyl or two cycloalkyl moieties as defined herein, or to a combination of one or more heterocyclyl and one or more cycloalkyl moiety, having one ring atom in common, i.e., the two rings are connected via one common ring atom. Some exemplary spirocyclic ring systems, yet non-limiting

[0057] As used herein and unless otherwise specified, the suffix “-ene” is used to describe a divalent group. Thus, any of the terms above can be modified with the suffix “-ene” to describe a divalent version of that moiety. For example, a divalent carbocycle is “carbocyclylene,” a divalent aryl ring is “arylene,” a divalent benzene ring is “phenylene,” a divalent heterocycle is “heterocyclylene,” a divalent heteroaryl ring is “heteroarylene,” a divalent alkyl chain is “alkylene,” a divalent alkenyl chain is “alkylene,” a divalent alkynyl chain is “alkynylene,” and so forth.

[0058] As used herein, “stereoisomer” or “optical isomer” refers to a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0059] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism,Attorney Ref: 41827-65010 (044WO) protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of this disclosure and the knowledge of the prior art.

[0060] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S -penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture.

[0061] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In other embodiments, the compound mixture has an (S) -enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5%, or more. In other embodiments, the compound mixture has an (R) -enantiomeric purity of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or more. In some other embodiments, the compound mixture has an (R) -enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5% or more.

[0062] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic / chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization orAttorney Ref: 41827-65010 (044WO) chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0063] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially.

[0064] As described herein, compounds of the disclosure may, when specified, contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,^N-R1, or ). In addition, in a polycyclic ring system, substituents may, unless“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their purification, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0065] As used herein, an embodiment that describes two variables form, together with the atoms they are attached to, an 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, refers to the number of rings formed. For example, in Formula (I):Attorney Ref: 41827-65010 (044WO)The ring systems formed by the variables are counted as follows:R3and R4form, together with the atoms they are attached to, a 10-atom fused bicyclic ring system with 3 heteroatoms. R7and R9form, together with the atoms they are attached to, a 4-atom cycloalkyl ring.

[0066] Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers.” For example, compounds including carbonyl -CH2C O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable. By way of example, the process of tautomerization is as follows:

[0067] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures ofAttorney Ref: 41827-65010 (044WO) diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers.Whenever the isomeric composition is unspecified, all possible isomers are included.

[0068] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0069] Those skilled in the art will appreciate that a bond designated as ~ in a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. For example, the following structure:is intended to encompass both

[0070] As used herein, “subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human.

[0071] As used herein, the term “treat,” “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0072] As used herein, “therapeutically effective amount,” “therapeutically effective amount or dose,” “therapeutically sufficient amount or dose,” “effective amount or dose,” or “sufficient amount or dose” are used interchangeably to refer to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques.

[0073] As used herein, the term “unsaturated” refers to a moiety has one or more units of unsaturation.

[0074] Unless otherwise specified, reference to an atom is meant to include isotopes of that atom. For example, reference to H is meant to include ’H,2H (i.e., D), and3H (i.e., T), and reference to C is meant to include12C and all isotopes of carbon (such as13C).3.2. CompoundsAttorney Ref: 41827-65010 (044WO)

[0075] The present embodiments provide compounds and pharmaceutically acceptable salts thereof, of Formula (I):wherein:- is a single bond or a double bond;R1is H or Ci-Ce alkyl;R2is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CR)o eOR2A, -C(O)R2A, -(C HR, „CO2R2. -(C HR, „OC(O)R2. -NO2, -CN, -N3, -(CH2)1. N( R2)( R21). -(C H2) > C(O)N( RA)( R21). -(CH2)0-6SR2A, and ring A;ring A is selected from C3-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9- membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C; orR1and R2form, along with the atoms they are attached to, a 5 - to 7- membered heterocycloalkyl substituted with 0, 1, or 2 R2C;each R2Aand R2Bare independently selected from H, Ci-Cg alkyl, -(CR)o eOH, -(CR)o eOCi-Ce alkyl, -C(O)H, -C(O)Ci-C6alkyl, -(CR)0 6CO2H, -(CR)0 6CO2Ci-C6alkyl, and C3-C8cycloalkyl; each R2Cis independently selected from Ci-Ce alkyl, halogen, -(CR)., „OH. -(CR).. OC-C, alkyl, oxo,-C(O)H, -C(O)Ci-C6alkyl, -(C )0^CO2H, -(CH2)O^C02CI-C6 alkyl, -NO2, -N3, -(CR)06NH(R2C1), -(CR).,, N(R2CI)(R2C2). -(C )O-6C(0)N(R2C1)(R2C2), and C3-C8spirocycloalkyl;each R2C1and R2C2are independently H or C1-C6alkyl;X1is NR1Aor CR1A,wherein R1Ais H,, Ci-Ce alkyl, or Ci-Ce haloalkyl;X2is N or C;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, l, or 2 R5;R4is selected from H, Ci-Cg alkyl, Ci-Cg haloalkyl, halogen, -(CR)o eOH, -(CH:),, „OC|-C„ alkyl, -C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0-6CO2H; or orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, andAttorney Ref: 41827-65010 (044WO) the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6R5ACO3H, - (CH2)1)„CO2CI-C„ alkyl, -(CH2)o 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)o6NHCI-C6alkyl, - (CH2)O^NHR5ACH2OH, -(CH2)O6NHR5ACO2H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6SH, -(CH2)O.6SR5A, -(CH2)O 6SO3H, -(CH2)O 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)0-6NH(CH2)I.4OP(O)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I.6OP(O)(H)(OH), -(CH2)O^P(0)(OH)2, -(CH2)O^P(0)(OC1-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)0^OP(O)(OH)(OCI-C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cn spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Cg alkyl, C4-C8 cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6NH2, -(CH2)0-6N(C1- C6alkyl)2, -(CH2).)„P(O)(OH)2. -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), -(CH2)O^OP(0)(OCI-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)o-eOH, -(CH2)o-eNH2, oxo, C3.s cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O eNHCi-Ce alkyl, oxo, C3-Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cn spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2),)., OP(O)(OH)2. -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH:),) „OP(O)(H)(OH). C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;Attorney Ref: 41827-65010 (044WO) each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)..,. OP(O)(OH)2. -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), and -(CH2)o6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;each R10, R11, and R12are hydrogen; orR12and X1form, along with the atoms they are attached to, a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl, and the 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 R13; and R10and R11are each hydrogen; andR13is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, and -(CH2)O^P(0)(OCI-C6alkyl)2.

[0076] In some embodiments, - is a single bond or a double bond. In some embodiments, - is a single bond. In some embodiments, - is a double bond.

[0077] In some embodiments, R1is H or Ci-Ce alkyl. In some embodiments, R1is H. In some embodiments, R1is Ci-Ce alkyl. In some embodiments, R1is Ci alkyl. In some embodiments, R1is C2 alkyl. In some embodiments, R1is C3 alkyl. In some embodiments, R1is C4 alkyl. In some embodiments, R1is C5 alkyl. In some embodiments, R1is C, alkyl.

[0078] In some embodiments, R2is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)o6OR2A(such as -OR2Aand -(CH2)I. OR27). -C(O)R2A, -(CH2).. „CO2R2A(such as -CO2R2Aand -(CH2)I6CO2R2A), -(CH2)..,, OC(O)R2A(such as -OC(O)R2Aand -(CH2)I, OC(O)R2). -NO2, -CN, -N3, -(CH2)0 6N(R2A)(R2B) (such as -N(R2A)(R2B) and -(CH2)I, N(R2)( R21)). -(CH2)0_6C(O)N(R2A)(R2B) (such as -C(O)N(R2A)(R2B) and -(CH2)I, C(O)N( R2)( R1)). -(CH2)o.6SR2A(such as -SR2Aand-(CH2)i-6SR2A), and ring A.

[0079] In some embodiments, R2is selected from Ci-Cg alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)0 6OR2A(such as -OR2Aand -(CH2)I, OR2A). -C(O)R2A, -(CH2)„, CO2R2A(such as -CO2R2Aand -(CH2)I6CO2R2A), -(CH2)„, OC(O)R2A(such as -OC(O)R2Aand -(CH2)I, OC(O)R2A). -NO2, -CN, -Ns, -(CH2)O-6N(R2A)(R2B) (such as -N(R2A)(R2B) and -(CH2)I, N(R2 A)( R21)). -(CH2)0-6C(O)N(R2A)(R2B) (such as -C(O)N(R2A)(R2B) and -(CH2)I, C(O)N( R2)( R1)). -(CH2)0-6SR2A(such as -SR2Aand-(CH2)i-eSR2A), and ring A.

[0080] In some embodiments, R2is Ci-Ce alkyl. In some embodiments, R2is Ci-Ce haloalkyl. In some embodiments, R2is C2-C6 alkenyl. In some embodiments, R2is C2-C6 alkynyl. In some embodiments, R2Attorney Ref: 41827-65010 (044WO) is -(CH:),). OR2(such as -OR2Aand -(CH2)I eOR2A). In some embodiments, R2is -C(O)R2A. In some embodiments, R2is -(CH2)o eCO2R2A(such as -CO2R2Aand -(CH2)I eCO2R2A).

[0081] In some embodiments, R2is -(CH2)o eOC(O)R2A(such as -OC(O)R2Aand -(CH:)! „OC(O)R2). In some embodiments, R2is -NO2. In some embodiments, R2is -CN. In some embodiments, R2is -N3. In some embodiments, R2is -(CH2)o^N(R2A)(R2B) (such as -N(R2A)(R2B) and -(CH2)I, N(R2)( R21)). In some embodiments, R2is -(CH2)o^C(0)N(R2A)(R2B) (such as -C(O)N(R2A)(R2B) and -(CH2)I- eC(O)N(R2A)(R2B)). In some embodiments, R2is -(CH2)o-eSR2A(such as -SR2Aand-(CH2)i-eSR2A). In some embodiments, R2is ring A.

[0082] In some embodiments, ring A is selected from C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cio aryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C

[0083] In some embodiments, ring A is Cs-Cs cycloalkyl. In some embodiments, ring A is C3 cycloalkyl. In some embodiments, ring A is C4 cycloalkyl. In some embodiments, ring A is C5 cycloalkyl. In some embodiments, ring A is Ce cycloalkyl. In some embodiments, ring A is C7 cycloalkyl. In some embodiments, ring A is Cs cycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0084] In some embodiments, ring A is Ce-Cs fused bicyclic cycloalkyl. In some embodiments, ring A is C5 fused bicyclic cycloalkyl. In some embodiments, ring A is Ce fused bicyclic cycloalkyl. In some embodiments, ring A is C7 fused bicyclic cycloalkyl. In some embodiments, ring A is Cs fused bicyclic cycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0085] In some embodiments, ring A is Ce-Cioaryl. In some embodiments, ring A is Cearyl. In some embodiments, ring A is C7aryl. In some embodiments, ring A is Cs aryl. In some embodiments, ring A is C9 aryl. In some embodiments, ring A is C10 aryl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0086] In some embodiments, ring A is a 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 3 -membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 4-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 5-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 6-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 7-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is an 8 -membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 9-membered heterocycloalkyl having one or more nitrogen atoms. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0087] In some embodiments, ring A is a 4- to 9-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 4-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 5-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 6-membered fusedAttorney Ref: 41827-65010 (044WO) bicyclic heterocycloalkyl. In some embodiments, ring A is a 7-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is an 8-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 9-membered fused bicyclic heterocycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0088] In some embodiments, R1and R2form, along with the atoms they are attached to, a 5- to 7-membered heterocycloalkyl independently substituted with 0, 1, or 2 R2C.

[0089] In some embodiments, R1and R2form, along with the atoms they are attached to, a 5 -membered heterocycloalkyl. In some embodiments, R1and R2form, along with the atoms they are attached to, a 6-membered heterocycloalkyl. In some embodiments, R1and R2form, along with the atoms they are attached to, a 7-membered heterocycloalkyl. In further embodiments, wherein the 5- to 7- membered heterocycloalkyl formed by R1and R2, along with the atoms they are attached to, is independently substituted with 0, 1, or 2 R2C.

[0090] In embodiments of any one of the above, each R2Aand R2Bare independently selected from H, Ci-Cg alkyl, -(CH2)0eOH (such as -OH and -(CH2) i, OH). -(CH2)0eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I6OCi-C6alkyl), -C(O)H, -C(O)Ci-C6alkyl, -(CH2)„, CO2H (such as -CO2H and -(CH2)I6CO2H), -(CH2)O_6C02CI-C6alkyl (such as -CO2Ci-C6alkyl and -(CH2)I^CO2CI-C6alkyl), and C3-C8cycloalkyl.

[0091] In some embodiments, R2Ais H. In some embodiments, R2Ais Ci-Cg alkyl. In some embodiments, R2Ais -(CH2),j„OH (such as -OH and -(CH2)I6OH). In some embodiments, R2Ais -(CH2)0eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I eOCi-Ce alkyl). In some embodiments, R2Ais -C(O)H. In some embodiments, R2Ais -C(O)Ci-Ce alkyl. In some embodiments, R2Ais -(CRf „CO2H (such as -CO2H and -(CH2)I eCO2H). In some embodiments, R2Ais -(CRf „CO2Ci-C„ alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I 6CO2Ci-Ce alkyl). In some embodiments, R2Ais C3-C8cycloalkyl.

[0092] In some embodiments, R2Bis H. In some embodiments, R2Bis Ci-Ce alkyl. In some embodiments, R2Bis -(CRf „OH (such as -OH and -(CH2)I eOH). In some embodiments, R2Bis -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I eOCi-Ce alkyl). In some embodiments, R2Bis -C(O)H. In some embodiments, R2Bis -C(O)Ci-Ce alkyl. In some embodiments, R2Bis -(CH2)0-eC02H (such as -CO2H and -(CH2)I eCO2H). In some embodiments, R2Bis -(CH2)o 6CO2Ci-Ce alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I 6CO2Ci-Ce alkyl). In some embodiments, R2Bis C3-C8cycloalkyl.

[0093] In embodiments of any one of the above, each R2Cis independently selected from Ci-Ce alkyl, halogen, -(CRf „OH (such as -OH and -(CH2)I eOH), -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I.. OCi-Ce alkyl), oxo, -C(O)H, -C(O)Ci-C6alkyl, -(CH2)„, CO2H (such as -CO2H and -(CH2)I eCO2H), -(CH2)0 6CO2Ci-C6alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I „CO2C|-C„ alkyl), -NO2, -N3, -(CH2)0 6NH(R2C1) (such as -NH(R2c1) and -(CH2)I6NH(R2c1)), -(CH2)„ „N(R2c1)(R2c2) (such as -N(R2C1)(R2C2) and -(CH2)I6N(R2c1)(R2c2)), -(CH2)„,. C(O)N(R2c1)(R2c2) (such as -C(O)N(R2c1)(R2c2) and -(CH2)I „C(O)N(R2c1)(R2c2)). and C3-C8spirocycloalkyl.

[0094] In some embodiments, R2Cis Ci-Cg alkyl. In some embodiments, R2Cis halogen. In some embodiments, R2Cis -(CH2)H „OH (such as -OH and -(CH2)I6OH). In some embodiments, R2Cis -(CH2)Q_Attorney Ref: 41827-65010 (044WO) eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I eOCi-Ce alkyl). In some embodiments, R2Cis oxo. In some embodiments, R2Cis -C(O)H. In some embodiments, R2Cis -C(O)Ci-Ce alkyl. In some embodiments, R2Cis -(CH:),) CO2H (such as -CO2H and -(CH2)I 6CO2H). In some embodiments, R2Cis -(CH2) ). CO2C1-C,, alkyl (such as -CO2C1-C6 alkyl and -(CH2)I eCChCi-Ce alkyl). In some embodiments, R2Cis -NO2. In some embodiments, R2Cis -N3. In some embodiments, R2Cis -(CH2)o eNH(R2c1) (such as -NH(R2C1) and -(CH2)I eNH(R2c1)). In some embodiments, R2Cis -(CH:),) „N(R2c1)(R2c2) (such as -N(R2C1)(R2C2) and -(CH2)I6N(R2c1)(R2c2)). In some embodiments, R2Cis -(CH2)o^C(0)N(R2c1)(R2c2) (such as -C(O)N(R2c1)(R2c2) and -(CH2)I eC(O)N(R2c1)(R2c2)). In some embodiments, R2Cis Cs-Cs spirocycloalkyl. In some embodiments, R2Cis C3 spirocycloalkyl. In some embodiments, R2Cis C4 spirocycloalkyl. In some embodiments, R2Cis C5 spirocycloalkyl. In some embodiments, R2Cis Ce spirocycloalkyl. In some embodiments, R2Cis C7 spirocycloalkyl. In some embodiments, R2Cis Cs spirocycloalkyl.

[0095] In embodiments of any one of the above, each R2c1and R2c2are independently H or Ci-Ce alkyl. In some embodiments, R2c1is H. In some embodiments, R2c1is Ci-Cg alkyl. In some embodiments, R2c1is Ci alkyl. In some embodiments, R2c1is C2 alkyl. In some embodiments, R2c1is C3 alkyl. In some embodiments, R2c1is C4 alkyl. In some embodiments, R2c1is C5 alkyl. In some embodiments, R2c1is C„ alkyl. In some embodiments, R2c2is H. In some embodiments, R2c2is Ci-Ce alkyl. In some embodiments, R2C2is Ci alkyl. In some embodiments, R2c2is C2 alkyl. In some embodiments, R2c2is C3 alkyl. In some embodiments, R2c2is C4 alkyl. In some embodiments, R2c2is C5 alkyl. In some embodiments, R2c2is Ce alkyl.

[0096] In some embodiments, X1is NR1Aor C(R1A)i-2. In some embodiments, X1is NR1A. In some embodiments, X1is CR1A. In some embodiments, X1is C(R1A)2.

[0097] In embodiments of any one of the above, R1Ais independently selected from H, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some embodiments, R1Ais H. In some embodiments, R1Ais Ci-Ce alkyl. In some embodiments, R1Ais Ci-Ce haloalkyl. In some embodiments, it will be understood to one of skill in the art that when X1is CR1A, the carbon atom is an sp2-hybridized carbon. In some embodiments, it will be understood to one of skill in the art that when X1is C(R1A)2, the carbon atom is a quaternary carbon. In some embodiments, it will be understood to one of skill in the art, that when X2is C, the carbon is sp2-hybridized.

[0098] In some embodiments, X2is N or C. In some embodiments, X2is N. In some embodiments, X2is C. In some embodiments, it will be understood to one of skill in the art, that when X2is C, the carbon is sp2-hybridized.

[0099] In some embodiments, R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cio aryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0100] In some embodiments, ring B is C4-C8 cycloalkyl. In some embodiments, ring B is C4 cycloalkyl. In some embodiments, ring B is C5 cycloalkyl. In some embodiments, ring B is Ce cycloalkyl. In someAttorney Ref: 41827-65010 (044WO) embodiments, ring B is C7 cycloalkyl. In some embodiments, ring B is Cs cycloalkyl. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0101] In some embodiments, ring B is Ce-Cioaryl. In some embodiments, ring B is Cearyl. In some embodiments, ring B is Criaryl. In some embodiments, ring B is Cs aryl. In some embodiments, ring B is C9 aryl. In some embodiments, ring B is C10 aryl. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0102] In some embodiments, ring B is a 3- to 9-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 3 -membered heterocycloalkyl having 1 or 2 heteroatoms which are N or O. In some embodiments, ring B is a 4-membered heterocycloalkyl having 1 or 2 heteroatoms which are N or O. In some embodiments, ring B is a 5 -membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 6-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 7-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is an 8-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 9-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0103] In some embodiments, ring B is a 3- to 9-membered monocyclic heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 4- to 7-membered bicyclic heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O.

[0104] In some embodiments, ring B is a 5- to 10-membered heteroaryl. In some embodiments, ring B is a 5 -membered heteroaryl. In some embodiments, ring B is a 6-membered heteroaryl. In some embodiments, ring B is a 7-membered heteroaryl. In some embodiments, ring B is an 8-membered heteroaryl. In some embodiments, ring B is a 9-membered heteroaryl. In some embodiments, ring B is a 10-membered heteroaryl. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0105] In some embodiments, R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH:),) OH (such as -OH and -(CH2) 1 OH). -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I eOCi-Ce alkyl), -C(O)H, -C(O)Ci-Ce alkyl, and -(CH:),), CO: H (such as -CO2H and -(CH:),. CCfH).

[0106] In some embodiments, R4is H. In some embodiments, R4is Ci-Ce alkyl. In some embodiments, R4is Ci-Ce haloalkyl. In some embodiments, R4is halogen. In some embodiments, R4is -(CH:),) OH (such as -OH and -(CH:)i, OH). In some embodiments, R4is -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH:): eOCi-Ce alkyl). In some embodiments, R4is -C(O)H. In some embodiments, R4is -C(O)Ci-Ce alkyl. In some embodiments, R4is -(CH:),), CO: H (such as -CO2H and -(CH2) 1, CO: H).

[0107] In some embodiments, R3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6. In some embodiments, the fused bicyclic or tricyclic heterocyclic ring has a quaternary nitrogen. In some embodiments, R3and R4form, together with the atoms they areAttorney Ref: 41827-65010 (044WO) attached to, an 8-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, a 9-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, a 10-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, an 11-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, a 12-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, a 13 -membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, a 14-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, R3and R4form, together with the atoms they are attached to, a 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O. In some embodiments, the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring formed by R3and R4, together with the atoms they are attached to, is fused to the pyridine ring to which R3and R4are attached. In further embodiments, wherein the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring formed by R3and R4, together with the atoms they are attached to, is independently substituted with 0, 1, 2, or 3 R6.

[0108] In embodiments of any one of the above, each R5is independently selected from -Ci-Ce alkyl, -(CH2)0-6OH (such as -OH and -(CH2)1-6OH), -(CH2)0-6CO2H (such as -CO2H and -(CH2)1-6CO2H), -(CH2)0-6R5ACO2H (such as -R5ACO2H and -(CH2)1-6R5ACO2H), -(CH2)0-6CO2C1-C6alkyl (such as -CO2C1-C6alkyl and -(CH2)1-6CO2C1-C6alkyl), -(CH2)0-6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1-6R5ACO2C1-C6alkyl), -(CH2)0-6NH2(such as -NH2and -(CH2)1-6NH2), -(CH2)0-6NHC1-C6alkyl (such as -NHCi-Ce alkyl and -(CH2)I eNHCi-Ce alkyl), -(CH2)0-eNHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)I^NHR5ACH2OH), -(CH2)0-6NHR5ACO2H (such as -NHR5ACO2H and -(CH2)I6NHR5ACO2H), -(CH2)O.6NH(CH2)I.6S03H (such as -NH(CH2)I.6SO3H and -(CH2)I6NH(CH2)I_6SO3H), -(CH2)O.6SH (such as -SH and -(CH2)I^SH), -(CH2)0.6SR5A(such as -SR5Aand -(CH2)I S R ). -(CH2)06SO3H (such as -SO3H and -(CH2)I6SO3H), -(CH2)0 6SO2NH2(such as -SO2NH2and -(CH2)I6SO2NH2), -(CH2)„ „SO2NHCI-C„ alkyl (such as -SO2NHCI-C6alkyl and -(CH,), „SO2NHCI-C„ alkyl), -(CH2)0.6NH(CH2)i.6OP(O)(OH)2(such as -NH(CH2)I.6OP(O)(OH)2and -(CH2)I6NH(CH2)I.6OP(O)(OH)2), -(CH2)0.6NH(CH2)I_4OP(O)(OH)(OCI-C6 alkyl) (such as - NH(CH2)I_4OP(O)(OH)(OCI-C6alkyl) and -(CH2)I45NH(CH2)I_4OP(O)(OH)(OCI-C6alkyl)), -(CH2)0.6NH(CH2)I_6OP(O)(H)(OH) (such as -NH(CH2)I.6OP(O)(H)(OH) and -(CH2)I6NH(CH2)I.6OP(O)(H)(OH)), -(CH2)„ „P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I^P(O)(OH)2), -(CH2)O 6P(O)(OCI-C6alkyl)2(such as -P(O)(OCi-C6alkyl)2and -(CH2)I 6P(O)(OCi-C6alkyl)2),-(CH2)0-6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I6OP(O)(OH)2), -(CH2)06OP(O)(OH)(OCI-C6alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I6OP(O)(OH)(OCI-C6Attorney Ref: 41827-65010 (044WO) alkyl)), -(CH2)O^OP(0)(OCI-C6alkyl)2(such as -OP(O)(OCi-C6alkyl)2and -(CH2)I6OP(O)(OCi-C6alkyl)2), -(CH2)0 6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)I^OP(O)(H)(OH)), C4-C8cycloalkyl, C5-C8 fused bicyclic cycloalkyl, C6-C12 spirocyclyl, C6-C10 aryl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -C1-C6 alkyl, C4-C8 cycloalkyl, C5-C8 fused bicyclic cycloalkyl, C6-C12 spirocyclyl, C6-C10 aryl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0109] In some embodiments, R5is -C1-C6 alkyl. In some embodiments, R5is -(CH2)0 6OH (such as -OH and -(CH2)I_6OH). In some embodiments, R5is -(CH2)0 6CO2H (such as -CO2H and -(CH2)I „CO2H). In some embodiments, R5is -(CH2)H „R CO2H (such as -R5ACO2H and -(CH2)I6R5ACO2H). In some embodiments, R5is -(CH2)06CO2G- alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I „CO2C|-C„ alkyl). In some embodiments, R5is -(CH2)0^R5ACO2CI- alkyl (such as -R5ACO2CI- alkyl and -(CH2)I6R5ACO2-C6 alkyl). In some embodiments, R5is -(CH2)0-6NH2(such as -NH2and -(CH2)1-6NH2). In some embodiments, R5is -(CH2f „NHCi-C„ alkyl (such as -NHG-G alkyl and -(CH2)I eNHG- alkyl). In some embodiments, R5is -(CH2)o eNHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)I eNHR5ACH2OH). In some embodiments, R5is -(CH2f „NHR CO2H (such as -NHR5ACO2H and -(CH2)I,, NHR CO2H). In some embodiments, R5is -(CH2)O-6NH(CH2)I.6S03H (such as -NH(CH2)1–6SO3H and -(CH2)I „NH(CH2)I.„SO3H). In some embodiments, R5is -(CH2)0-eSH (such as -SH and -(CH2) 1 „SH). In some embodiments, R5is -(CH2)0-eSR5A(such as -SR5Aand -(CH2)I eSR5A). In some embodiments, R5is -(CH2)o 6SO3H (such as -SO3H and -(CH2) 1.. SOoH), In some embodiments, R5is -(CH2)U. SO2NH2(such as -SO2NH2and -(CH2)I eSO2NH2). In some embodiments, R5is -(CH2)o 6SO2NHG- alkyl (such as -SO2NHG-G alkyl and -(CH2)I „SO2NHCI-C, alkyl). In some embodiments, R5is -(CH2)O-6NH(CH2)I.60P(0)(OH)2(such as -NH(CH2)I.6OP(O)(OH)2and -(CH2)I 6NH(CH2)i 6OP(O)(OH)2). In some embodiments, R5is -(CH2)O-6NH(CH2)I.4OP(0)(OH)(OCI-C6 alkyl) (such as - NH(CH2)I.4OP(O)(OH)(OCI-C6alkyl) and -(CH2),45NH(CH2)i.4OP(O)(OH)(OCi-C6alkyl)). In some embodiments, R5is -(CH2)O-6NH(CH2)I.60P(0)(H)(OH) (such as -NH(CH2)I.6OP(O)(H)(OH) and -(CH2)I,, NH(CH2)I.,, OP(O)(H)(OH)). In some embodiments, R5is -(CH2)o eP(O)(OH)2(such as -P(O)(OH)2and -(CH2)I eP(O)(OH)2). In some embodiments, R5is -(CH2)o eP(O)(OCi-Ce alkyl)2(such as -P(O)(OCi-Ce alkyl)2and -(CH2)I eP(O)(OCi-Ce alkyl)2). In some embodiments, R5is -(CH2)o eOP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I „OP(O)(OH)2). In some embodiments, R5is -(CH2)o6OP(O)(OH)(OG-C6alkyl) (such as -OP(O)(OH)(OG-C6alkyl) and -(CH2)I6OP(O)(OH)(OCI-C6alkyl)). In some embodiments, R5is -(CH2)o eOP(O)(OCi-Ce alkyl)2(such as -OP(O)(OCi-Ce alkyl)2and -(CH2) 1 „OP(O)(OCi-C„ alkyl)2). In some embodiments, R5is -(CH2)0-6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)1–6OP(O)(H)(OH)). In some embodiments, R5is C4-Cs cycloalkyl. In some embodiments, R5is C5-C8 fused bicyclic cycloalkyl. In some embodiments, R5is C6-C12 spirocyclyl. In some embodiments, R5is C6-C10 aryl. In some embodiments, R5is 5- to 9-membered heterocycloalkyl. In some embodiments, R5is 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is 6- toAttorney Ref: 41827-65010 (044WO) 12-membered hetero-spirocyclyl. In some embodiments, R5is 5- to 10-membered heteroaryl. In further embodiments, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0110] In some embodiments, R5is -Ci-Ce alkyl. In some embodiments, R5is Ci alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, R5is C4 alkyl. In some embodiments, R5is C5 alkyl. In some embodiments, R5is C, alkyl. In further embodiments, wherein -Ci-Ce alkyl is independently substituted with 0, 1, or 2 R5B.

[0111] In some embodiments, R5is C4-C8 cycloalkyl. In some embodiments, R5is C4 cycloalkyl. In some embodiments, R5is C5 cycloalkyl. In some embodiments, R5is C, cycloalkyl. In some embodiments, R5is C7 cycloalkyl. In some embodiments, R5is Cs cycloalkyl. In further embodiments, wherein C4-C8 cycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0112] In some embodiments, R5is C5-C8fused bicyclic cycloalkyl. In some embodiments, R5is C5fused bicyclic cycloalkyl. In some embodiments, R5is C6fused bicyclic cycloalkyl. In some embodiments, R5is C7fused bicyclic cycloalkyl. In some embodiments, R5is Cs fused bicyclic cycloalkyl. In further embodiments, wherein C -C’s fused bicyclic cycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0113] In some embodiments, R5is Ce-Cn spirocyclyl. In some embodiments, R5is C6spirocyclyl. In some embodiments, R5is C7 spirocyclyl. In some embodiments, R5is Cs spirocyclyl. In some embodiments, R5is C9 spirocyclyl. In some embodiments, R5is C10 spirocyclyl. In some embodiments, R5is Ci 1 spirocyclyl. In some embodiments, R5is C12 spirocyclyl. In further embodiments, wherein C6-C12spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0114] In some embodiments, R5is Ce-Cioaryl. In some embodiments, R5is Cearyl. In some embodiments, R5is C7aryl. In some embodiments, R5is Csaryl. In some embodiments, R5is Cgaryl. In some embodiments, R5is Cioaryl. In further embodiments, wherein Ce-Cioaryl is independently substituted with 0, 1, or 2 R5B.

[0115] In some embodiments, R5is a 5- to 9-membered heterocycloalkyl. In some embodiments, R5is a 5-membered heterocycloalkyl. In some embodiments, R5is a 6-membered heterocycloalkyl. In some embodiments, R5is a 7-membered heterocycloalkyl. In some embodiments, R5is an 8-membered heterocycloalkyl. In some embodiments, R5is a 9-membered heterocycloalkyl. In further embodiments, wherein the 5- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0116] In some embodiments, R5is a 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 7-membered bicyclic heterocycloalkyl. In some embodiments, R5is an 8-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 9-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 10-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 11-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 12-Attorney Ref: 41827-65010 (044WO) membered bicyclic heterocycloalkyl. In further embodiments, wherein the 7- to 12-membered bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0117] In some embodiments, R5is a 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is a 6-membered hetero-spirocyclyl. In some embodiments, R5is a 7-membered hetero-spirocyclyl. In some embodiments, R5is an 8-membered hetero-spirocyclyl. In some embodiments, R5is a 9-membered hetero-spirocyclyl. In some embodiments, R5is a 10-membered hetero-spirocyclyl. In some embodiments, R5is a 11 -membered hetero-spirocyclyl. In some embodiments, R5is a 12-membered hetero-spirocyclyl. In further embodiments, wherein the 6- to 12-membered hetero-spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0118] In some embodiments, R5is a 5- to 10-membered heteroaryl. In some embodiments, R5is a 5-membered heteroaryl. In some embodiments, R5is a 6-membered heteroaryl. In some embodiments, R5is a 7-membered heteroaryl. In some embodiments, R5is an 8-membered heteroaryl. In some embodiments, R5is a 9-membered heteroaryl. In some embodiments, R5is a 10-membered heteroaryl. In further embodiments, wherein the 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0119] In embodiments of any one of the above, each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)u OH (such as -OH and -(CH2)I eOH), -(CH2)0C O H (such as -CO2H and -(CH2)I6CO2H), -(CH2)O 6R5ACO2H (such as -R5ACO2H and -(CH2)I6R5ACO2H), -(CH2)0^CO2CI-C6alkyl (such as -CO2Ci-C6alkyl and -(CH2)I^CO2CI-C6alkyl), -(CH2)0 6R5ACO2CI-C6alkyl (such as -R5ACO2CI-C6alkyl and -(CH2)I6R5ACO2CI-C6alkyl), -(CH2)0.6NH2(such as -NH2and -(CH2)I „NH2). -(CH2)0^N(CI-Ce alkyl)2(such as -N(Ci-Ce alkyl)2and -(CH2)i-6N(Ci-Ce alkyl)2), -(CH2)u. P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I6P(O)(OH)2), -(CH2)0-6P(O)(OC1-C6alkyl)2(such as -P(O)(OCi-C6alkyl)2and -(CH2)I^P(O)(OCI-C6alkyl)2),-(CH2)0-6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I^OP(O)(OH)2), -(CH2)„ „OP(O)(OH)(OCI-C.1alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I^OP(O)(OH)(OCI-C6alkyl)), -(CH2)0^OP(O)(OCI-C6alkyl)2(such as -OP(O)(OCi-C6alkyl)2and -(CH2)I^OP(O)(OCI-C6alkyl)2), -(CH2)0 6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)I^OP(O)(H)(OH)), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C3-C8cycloalkyl, C6-C10aryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0120] In some embodiments, R6is deuterium. In some embodiments, R6is -Ci-Cg alkyl. In some embodiments, R6is -(CH2)0 6OH (such as -OH and -(CH2)I „OH). In some embodiments, R6is -(CH2)0eCO2H (such as -CO2H and -(CH2)I6CO2H). In some embodiments, R6is -(CH2)0 6R5ACO2H (such as -R5ACO2H and -(CH2)I „RA'CO2H). In some embodiments, R6is -(CH2)H „CO2C|-C„ alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I „CO2C|-C„ alkyl). In some embodiments, R6is -(CH2)H,, R 'CO2C|-C„ alkyl (such as -R5ACO2Ci-Ce alkyl and -(CH2)I,, RA'C02Ci-C,, alkyl). In some embodiments, R6is -(CH2)0-6NH2(such as -NH2and -(CH2)I eNH2). In some embodiments, R6is -(CH2)0-6N(Ci-Ce alkyl)2(such as -N(Ci-Ce alkyl)2and -(CH2)I^N(CI-C6 alkyl)2). In some embodiments, R6is -(CH2)u. P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I „P(O)(OH)2). In some embodiments, R6is -(CH2)0-6P(0)(OCi-Ce alkyl)2(such as -P(O)(OCi-Ce alkyl)2and -(CH2)I „P(O)(OCi-C„ alkyl)2). In some embodiments, R6is -(CH2)0-Attorney Ref: 41827-65010 (044WO) eOP(O)(OH)2 (such as -0P(0)(0H)2 and -(CH2) i 0P(0)(0H)2). In some embodiments, R6is -(CH2)o6OP(O)(OH)(OCI-C6alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I6OP(O)(OH)(OCI-C6alkyl)). In some embodiments, R6is -(CH2)o 6OP(O)(OCi-Ce alkyl)2 (such as -OP(O)(OCi-Ce alkyl)2 and -(CH2) i „OP(O)(OCI-C„ alkyl)2). In some embodiments, R6is -(CH2)0–6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2) i. O P(O)(H)(OH)). In some embodiments, R6is Cs-Cs cycloalkyl. In some embodiments, R6is Ce-Cioaryl. In some embodiments, R6is 3- to 9-membered heterocycloalkyl. In further embodiments, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0121] In some embodiments, R6is -Ci-Cg alkyl. In some embodiments, R6is Ci alkyl. In some embodiments, R6is C2 alkyl. In some embodiments, R6is C3 alkyl. In some embodiments, R6is C4 alkyl. In some embodiments, R6is C5 alkyl. In some embodiments, R6is Ce alkyl. In further embodiments, wherein -Ci-Cg alkyl is independently substituted with 0, 1, or 2 R5B.

[0122] In some embodiments, R6is Cs-Cs cycloalkyl. In some embodiments, R6is C3 cycloalkyl. In some embodiments, R6is C4 cycloalkyl. In some embodiments, R6is C5 cycloalkyl. In some embodiments, R6is Ce cycloalkyl. In some embodiments, R6is C7 cycloalkyl. In some embodiments, R6is C8cycloalkyl. In further embodiments, wherein C3-C8 cycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0123] In some embodiments, R6is Ce-Cioaryl. In some embodiments, R6is Cearyl. In some embodiments, R6is C?aryl. In some embodiments, R6is C8aryl. In some embodiments, R6is C aryl. In some embodiments, R6is Cioaryl. In further embodiments, wherein Ce-Cioaryl is independently substituted with 0, 1, or 2 R5B.

[0124] In some embodiments, R6is a 3- to 9-membered heterocycloalkyl. In some embodiments, R6is a 3-membered heterocycloalkyl. In some embodiments, R6is a 4-membered heterocycloalkyl. In some embodiments, R6is a 5 -membered heterocycloalkyl. In some embodiments, R6is a 6-membered heterocycloalkyl. In some embodiments, R6is a 7-membered heterocycloalkyl. In some embodiments, R6is an 8-membered heterocycloalkyl. In some embodiments, R6is a 9-membered heterocycloalkyl. In further embodiments, wherein the 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0125] In some embodiments, R5Ais a Ci-Ce aliphatic alkyl chain substituted with one or more halogens. In some embodiments, R5Ais a Ci-Ce aliphatic alkyl chain substituted with one or more -(CH2)o eOH (such as -OH and -(CH2)I OH). In some embodiments, R5Ais a Ci-Ce aliphatic alkyl chain substituted with one or more -(CH2)0-6NH2 (such as -NH2and -(CH2)I-6NH2). In some embodiments, R5Ais a Ci-Cg aliphatic alkyl chain substituted with one or more oxo. In some embodiments, R5Ais a Ci-Cg aliphatic alkyl chain substituted with one or more C3-8cycloalkyl. In some embodiments, R5Ais a Ci-Cg aliphatic alkyl chain substituted with one or more 3- to 9-membered heterocycloalkyl.

[0126] In some embodiments, R5Ais a Ci aliphatic alkyl chain. In some embodiments, R5Ais a C2 aliphatic alkyl chain. In some embodiments, R5Ais a C3 aliphatic alkyl chain. In some embodiments, R5Ais a C4 aliphatic alkyl chain. In some embodiments, R5Ais a C5 aliphatic alkyl chain. In someAttorney Ref: 41827-65010 (044WO) embodiments, R5Ais a C, aliphatic alkyl chain. In further embodiments, wherein the Ci, C2, C3, C4, C5, or C„ aliphatic alkyl chain is substituted with one or more groups selected from halogen, -(CH2)o-eOH (such as -OH and -(CH2)I eOH), -(CH2)0–6NH2(such as -NH2 and -(CH2)1–6NH2), oxo, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl.

[0127] In embodiments of any one of the above, each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH (such as -OH and -(CH2)I eOH), -(CH2)o 6CO2H (such as -CO2H and -(CH2)I 6CO2H), -(CH2)O 6CO2C1-C6 alkyl (such as -CO2C1-C6 alkyl and -(CH2)I. CO2C1-C,, alkyl), -(CH2)o eNH2(such as -NH2 and -(CH2)1–6NH2), -(CH:),),, NHCi-C, alkyl (such as -NHCi-Ce alkyl and -(CH2)i-eNHCi-Ce alkyl), oxo, Cs-Cs cycloalkyl, Ce-Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cio aryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C’s-C’s cycloalkyl, Cs-C’s fused bicyclic cycloalkyl, Ce-Cn spirocyclyl, Ce-C10 aryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C.

[0128] In some embodiments, R5Bis -Ci-Ce alkyl. In some embodiments, R5Bis halogen. In some embodiments, R5Bis -(CH2)0-60H (such as -OH and -(CH2)I-6OH). In some embodiments, R5Bis -(CH2)o 6CO2H (such as -CO2H and -(CH2)I 6CO2H). In some embodiments, R5Bis -(CH2)u. CO2C1-C,, alkyl (such as -CO2C1-C6 alkyl and -(CH2)1–6CO2C1-C6alkyl). In some embodiments, R5Bis -(CH2)0–6NH2(such as -NH2 and -(CH2)1–6NH2). In some embodiments, R5Bis -(CH:),),, NHC’i-C„ alkyl (such as -NHCi-C, alkyl and -(CH:): eNHCi-Ce alkyl). In some embodiments, R5Bis oxo. In some embodiments, R5Bis Cs-Cs cycloalkyl. In some embodiments, R5Bis C5-C8fused bicyclic cycloalkyl. In some embodiments, R5Bis C6-C12 spirocyclyl. In some embodiments, R5Bis Ce-Cioaryl. In some embodiments, R5Bis 3- to 9-membered heterocycloalkyl. In some embodiments, R5Bis 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5Bis 5- to 10-membered heteroaryl. In further embodiments, wherein each of the C3-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C.

[0129] In some embodiments, R5Bis Cs-Cs cycloalkyl. In some embodiments, R5Bis C3 cycloalkyl. In some embodiments, R5Bis C4 cycloalkyl. In some embodiments, R5Bis C5 cycloalkyl. In some embodiments, R5Bis Ce cycloalkyl. In some embodiments, R5Bis C7 cycloalkyl. In some embodiments, R5Bis C8cycloalkyl. In further embodiments, wherein Cs-Cs cycloalkyl is independently substituted with 0, l, or2 R5C.

[0130] In some embodiments, R5Bis C -Cs fused bicyclic cycloalkyl. In some embodiments, R5Bis C5 fused bicyclic cycloalkyl. In some embodiments, R5Bis Ce fused bicyclic cycloalkyl. In some embodiments, R5Bis C7 fused bicyclic cycloalkyl. In some embodiments, R5Bis Cs fused bicyclic cycloalkyl. In further embodiments, wherein C -Cs fused bicyclic cycloalkyl is independently substituted with 0, l, or2 R5C.Attorney Ref: 41827-65010 (044WO)

[0131] In some embodiments, R5Bis C6-C12spirocyclyl. In some embodiments, R5Bis C, spirocyclyl. In some embodiments, R5Bis C? spirocyclyl. In some embodiments, R5Bis Cs spirocyclyl. In some embodiments, R5Bis Cg spirocyclyl. In some embodiments, R5Bis Cio spirocyclyl. In some embodiments, R5Bis Cn spirocyclyl. In some embodiments, R5Bis C12 spirocyclyl. In further embodiments, wherein C6-C12spirocyclyl is independently substituted with 0, 1, or 2 R5C.

[0132] In some embodiments, R5Bis Ce-Cioaryl. In some embodiments, R5Bis Cearyl. In some embodiments, R5Bis Cgaryl. In some embodiments, R5Bis Csaryl. In some embodiments, R5Bis C aryl. In some embodiments, R5Bis Cioaryl. In further embodiments, wherein Ce-Cioaryl is independently substituted with 0, 1, or 2 R5C.

[0133] In some embodiments, R5Bis a 3- to 9-membered heterocycloalkyl. In some embodiments, R5Bis a 3-membered heterocycloalkyl. In some embodiments, R5Bis a 4-membered heterocycloalkyl. In some embodiments, R5Bis a 5-membered heterocycloalkyl. In some embodiments, R5Bis a 6-membered heterocycloalkyl. In some embodiments, R5Bis a 7-membered heterocycloalkyl. In some embodiments, R5Bis an 8-membered heterocycloalkyl. In some embodiments, R5Bis a 9-membered heterocycloalkyl. In further embodiments, wherein the 3- to 9-membered heterocycloalkyl is independently substituted with 0, l, or 2 R5C.

[0134] In some embodiments, R5Bis a 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5Bis a 7-membered bicyclic heterocycloalkyl. In some embodiments, R5Bis an 8-membered bicyclic heterocycloalkyl. In some embodiments, R5Bis a 9-membered bicyclic heterocycloalkyl. In some embodiments, R5Bis a 10-membered bicyclic heterocycloalkyl. In some embodiments, R5Bis a 11 -membered bicyclic heterocycloalkyl. In some embodiments, R5Bis a 12-membered bicyclic heterocycloalkyl. In further embodiments, wherein the 7- to 12-membered bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R5C.

[0135] In some embodiments, R5Bis a 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5Bis a 6-membered hetero-spirocyclyl. In some embodiments, R5Bis a 7-membered hetero-spirocyclyl. In some embodiments, R5Bis an 8-membered hetero-spirocyclyl. In some embodiments, R5Bis a 9-membered hetero-spirocyclyl. In some embodiments, R5Bis a 10-membered hetero-spirocyclyl. In some embodiments, R5Bis a 11-membered hetero-spirocyclyl. In some embodiments, R5Bis a 12-membered hetero-spirocyclyl. In further embodiments, wherein the 6- to 12-membered hetero-spirocyclyl is independently substituted with 0, 1, or 2 R5C.

[0136] In some embodiments, R5Bis a 5 - to 10-membered heteroaryl. In some embodiments, R5Bis a 5-membered heteroaryl. In some embodiments, R5Bis a 6-membered heteroaryl. In some embodiments, R5Bis a 7-membered heteroaryl. In some embodiments, R5Bis an 8-membered heteroaryl. In some embodiments, R5Bis a 9-membered heteroaryl. In some embodiments, R5Bis a 10-membered heteroaryl. In further embodiments, wherein the 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C.

[0137] In embodiments of any one of the above, each R5Cis independently selected from -Ci-Cg alkyl, halogen, -(CH2)0-60H (such as -OH and -(CH2)I eOH), -(CH2)0 6CO2H (such as -CO2H and -(CH2)IAttorney Ref: 41827-65010 (044WO) 6CO2H), -(CH2)O 6CO2C1-C6 alkyl (such as -CO2C1-C6 alkyl and -(CH2)I. CO2C1-C,, alkyl), -(CH2)o eNH2(such as -NH2and -(CH2)I6NH2), -(CH2)o^S03H (such as -SO3H and -(CH2)I6SO3H), -(CH2)o6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I^OP(O)(OH)2), -(CH2)o 6OP(O)(OH)(OCI-C6alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I^OP(O)(OH)(OCI-C6alkyl)), -(CH2)„ „OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)I eOP(O)(H)(OH)), C3-C8cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D.

[0138] In some embodiments, R5Cis -Ci-Cg alkyl. In some embodiments, R5Cis halogen. In some embodiments, R5Cis -(CH2)o eOH (such as -OH and -(CH2)I eOH). In some embodiments, R5Cis -(CH2)o 6CO2H (such as -CO2H and -(CH2)I-6CO2H). In some embodiments, R5Cis -(CH2)u „CO2C|-C„ alkyl (such as -CO2C1-C6 alkyl and -(CH2) 1 „CO2C|-C„ alkyl). In some embodiments, R5Cis -(CH2)0-6NH2 (such as -NH2and -(CH2)I-6NH2). In some embodiments, R5Cis -(CH2)u „SO3H (such as -SO3H and -(CH2)I „SO3H). In some embodiments, R5Cis -(CH2)u „OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I 6OP(O)(OH)2). In some embodiments, R5Cis -(CH2)u, OP(O)(OH)(OC|-C„ alkyl) (such as -OP(O)(OH)(OCi-Ce alkyl) and -(CH2)I 6OP(O)(OH)(OCi-Ce alkyl)). In some embodiments, R5Cis -(CH2)u., OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2) i. O P(O)(H)(O H)). In some embodiments, R5Cis C3-C8cycloalkyl. In some embodiments, R5Cis Ce-Cioaryl. In some embodiments, R5Cis 3- to 9-membered heterocycloalkyl. In some embodiments, R5Cis 5- to 10-membered heteroaryl. In further embodiments, wherein each of the C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D.

[0139] In some embodiments, R5Cis C3-C8cycloalkyl. In some embodiments, R5Cis C3cycloalkyl. In some embodiments, R5Cis C4 cycloalkyl. In some embodiments, R5Cis C5 cycloalkyl. In some embodiments, R5Cis C„ cycloalkyl. In some embodiments, R5Cis C7 cycloalkyl. In some embodiments, R5Cis C8cycloalkyl. In further embodiments, wherein C3-C8cycloalkyl is independently substituted with 0, 1, or 2 R5D.

[0140] In some embodiments, R5Cis Ce-Cioaryl. In some embodiments, R5Cis Cearyl. In some embodiments, R5Cis C?aryl. In some embodiments, R5Cis C8aryl. In some embodiments, R5Cis C aryl. In some embodiments, R5Cis Cioaryl. In further embodiments, wherein Ce-Cioaryl is independently substituted with 0, 1, or 2 R5D.

[0141] In some embodiments, R5Cis a 3- to 9-membered heterocycloalkyl. In some embodiments, R5Cis a 3-membered heterocycloalkyl. In some embodiments, R5Cis a 4-membered heterocycloalkyl. In some embodiments, R5Cis a 5-membered heterocycloalkyl. In some embodiments, R5Cis a 6-membered heterocycloalkyl. In some embodiments, R5Cis a 7-membered heterocycloalkyl. In some embodiments, R5Cis an 8-membered heterocycloalkyl. In some embodiments, R5Cis a 9-membered heterocycloalkyl. In further embodiments, wherein the 3- to 9-membered heterocycloalkyl is independently substituted with 0, l, or 2 R5D.

[0142] In embodiments of any one of the above, each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH (such as -OH and -(CH2)I eOH), -(CH2)0-6CO2H (such as -CO2H and -(CH2)IAttorney Ref: 41827-65010 (044WO) 6CO2H), -(CH2)O 6CO2C1-C6 alkyl (such as -CO2C1-C6 alkyl and -(CH2)I. CO2C1-C,, alkyl), -(CH2)o eNH2(such as -NH2and -(CH2)I6NH2), -(CH2)o^S03H (such as -SO3H and -(CH2)I6SO3H), -(CH2)o6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I^OP(O)(OH)2), -(CH2)o 6OP(O)(OH)(OCI-C6alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I^OP(O)(OH)(OCI-C6alkyl)), and -(CH2)o6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)I, OP(O)(H)(OH)).

[0143] In some embodiments, R5Dis -Ci-Ce alkyl. In some embodiments, R5Dis halogen. In some embodiments, R5Dis -(CH2)o eOH (such as -OH and -(CH2)I eOH). In some embodiments, R5Dis -(CH2)o 6CO2H (such as -CO2H and -(CH2)I eCO2H). In some embodiments, R5Dis -(CH2)o 6CO2Ci-Ce alkyl (such as -CO2C1-C6 alkyl and -(CH2)1–6CO2C1-C6alkyl). In some embodiments, R5Dis -(CH2)o eNH2(such as -NH2and -(CH2)I-6NH2). In some embodiments, R5Dis -(CH2)o eSO3H (such as -SO3H and -(CH2)I „SO3H). In some embodiments, R5Dis -(CH2)o eOP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I 6OP(O)(OH)2). In some embodiments, R5Dis -(CH2)o 6OP(O)(OH)(OCi-Ce alkyl) (such as -OP(O)(OH)(OCi-Ce alkyl) and -(CH2)I 6OP(O)(OH)(OCi-Ce alkyl)). In some embodiments, R5Dis -(CH2)„,. OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)I, OP(O)(H)(OH)).

[0144] In some embodiments, R7is hydrogen. In some embodiments, R8is hydrogen. In some embodiments, R9is hydrogen. In some embodiments, R7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen. In some embodiments, R7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen. In some embodiments, R8and R9form, along with the atoms they are attached to, a 3- to 6-membered cycloalkyl, and R7is hydrogen.

[0145] In some embodiments, R10is hydrogen. In some embodiments, R11is hydrogen. In some embodiments, R12is hydrogen. In some embodiments, R10and R11are each hydrogen. In some embodiments, R12and X1form, along with the atoms they are attached to, a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl, and the 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 R13. In some embodiments, the heterocycloalkyl has a quaternary nitrogen. In some embodiments, R12and X1form, along with the atoms they are attached to, a 4-membered cycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 5-membered cycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 6-membered cycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 7-membered cycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 4-membered heterocycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 5 -membered heterocycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 6-membered heterocycloalkyl. In some embodiments, R12and X1form, along with the atoms they are attached to, a 7-membered heterocycloalkyl. In further embodiments, wherein the 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl formed by R12and X1, along with the atoms they are attached to, is independently substituted with 0, 1, 2, 3, or 4 R13.Attorney Ref: 41827-65010 (044WO)

[0146] In some embodiments, R13is deuterium. In some embodiments, R13is -Ci-Ce alkyl. In some embodiments, R13is -(CH2)o eOH. In some embodiments, R13is -(CH:),). CO2H. In some embodiments, R13is -(CH2)O-6R5ACC>2H. In some embodiments, R13is -(CH2)o 6CO2C1-C6 alkyl. In some embodiments, R13is -(CH2)O-6R5ACC>2CI-C6 alkyl. In some embodiments, R13is -(CH:),) „P(O)(OH)2. In some embodiments, R13is -(CH2)o 6P(O)(OCi-Ce alkyl)2.

[0147] In some embodiments, the compound of Formula (I) is represented by Formula (I -a):wherein:X1, R1A, X2, R5A, R5B, R5C, and R5Dare as defined as in Formula (I);ring A is selected from C3-C6 cycloalkyl, Cs-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl;each R2Cis independently selected from C1-C3 alkyl, halogen, -(CH ) ) OH. -(CH ) ). OCi-C,, alkyl, oxo, -C(O)C1-C6alkyl, -(CH2)0-6CO2H, -(CH2) ^CO2Ci-C6alkyl, -(CH2)0-6NH(R2C1), -(CH2)1-5N(R2C1)(R2C2), -N(R2C1)(R2C2), and -(CH2)0-6C(O)N(R2C1)(R2C2);each R2C1and R2C2are independently H or C1-C3alkyl;R4is H;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 8-membered heterocycloalkyl, and 5- to 9-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;each R5is independently selected from -C2-C6 alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o6R5ACO2H, -(CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)o.6NH2, -(CH2)„. NHC C. alkyl, -(CH2)0 6NHR5ACH2OH, -(CH2)O^NHR5AC02H, -(CH2)0.6NH(CH2)1.6SO3H, -(CH2)O.6SH, - (CH2)O.6SR5A, -(CH2)O 6SO3H, -(CH2)06SO2NH2, -(CH2)„,. SO2NHCI-C,1alkyl, -(CH2)O-6NH(CH2)I.6OP(O)(OH)2, -(CH2)O.6NH(CH2)I.40P(0)(OH)(OCI-C6alkyl), -(CH2)O.6NH(CH2)I.60P(0)(H)(OH), - (CH2)O^P(0)(OH)2, -(CH2)O^P(0)(OC1-C6alkyl)2, -(CH2)0^OP(O)(OH)2, -(CH2)0^OP(O)(OH)(OC1- C6alkyl), -(CH2)o 6OP(O)(OCi-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), -C4-C8cycloalkyl, -CH2-(C3-C8cycloalkyl), Cs-C8fused bicyclic cycloalkyl, -CH2-(C5-C8fused bicyclic cycloalkyl), C6-C12spirocyclyl, Ce-Cioaryl, -CH2-(C6-Cioaryl), 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9- membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, -CH2-(7-to 12-Attorney Ref: 41827-65010 (044WO) membered bicyclic heterocycloalkyl), 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl and -CH2-(5- to 10-membered heteroaryl), wherein each of the -C2-C6 alkyl, C4-C8 cycloalkyl, G-G fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; andn is 0, 1, or 2.

[0148] In some embodiments, ring A is selected from C3- cycloalkyl, -G fused bicyclic cycloalkyl, G-Go aryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C

[0149] In some embodiments, ring A is G-G cycloalkyl. In some embodiments, ring A is C3 cycloalkyl. In some embodiments, ring A is C4 cycloalkyl. In some embodiments, ring A is C5 cycloalkyl. In some embodiments, ring A is Ce cycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0150] In some embodiments, ring A is Ce-Cs fused bicyclic cycloalkyl. In some embodiments, ring A is C5 fused bicyclic cycloalkyl. In some embodiments, ring A is Ce fused bicyclic cycloalkyl. In some embodiments, ring A is C7 fused bicyclic cycloalkyl. In some embodiments, ring A is Cs fused bicyclic cycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0151] In some embodiments, ring A is Ce-Cioaryl. In some embodiments, ring A is Cearyl. In some embodiments, ring A is Garyl. In some embodiments, ring A is Cs aryl. In some embodiments, ring A is C9 aryl. In some embodiments, ring A is C10 aryl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0152] In some embodiments, ring A is a 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 3 -membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 4-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 5 -membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 6-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 7-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is an 8-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 9-membered heterocycloalkyl having one or more nitrogen atoms. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0153] In some embodiments, ring A is a 4- to 9-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 4-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 5-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 6-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 7-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is an 8-membered fused bicyclic heterocycloalkyl. InAttorney Ref: 41827-65010 (044WO) some embodiments, ring A is a 9-membered fused bicyclic heterocycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0154] In embodiments of any one of the above, each R2Cis independently selected from C1-C3 alkyl, halogen, -(CH:),) OH (such as -OH and -(CH2)I eOH), -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)1^OC1-C6alkyl), oxo, -C(O)Ci-Ce alkyl, -(CH2)o 6CO2H (such as -CO2H and -(CH:)! CO2H). -(CH2)O^C02CI-C6alkyl (such as -CO2Ci-C6alkyl and -(CH2)I 6CO2Ci-C6alkyl), -(CH2)0-6NH(R2C1) (such as -NH(R2C1) and -(CH2)I6NH(R2c1)), -(CH2)I5N(R2c1)(R2c2), -N(R2c1)(R2c2), and -(CH2)o6C(O)N(R2C1)(R2C2) (such as -C(O)N(R2c1)(R2c2) and -(CH2)I6C(O)N(R2c1)(R2c2)).

[0155] In some embodiments, R2Cis C1-C3 alkyl. In some embodiments, R2Cis halogen. In some embodiments, R2Cis -(CH:),) OH (such as -OH and -(CH:): eOH). In some embodiments, R2Cis -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH:): eOCi-Ce alkyl). In some embodiments, R2Cis oxo. In some embodiments, R2Cis -C(O)Ci-Ce alkyl. In some embodiments, R2Cis -(CH:),), CO: H (such as -CO2H and -(CH2)I6CO2H). In some embodiments, R2Cis -(CH2)o 6CO2C1-C6 alkyl (such as -CO2C1-C6 alkyl and -(CH2)I 6CO2C1-C6 alkyl). In some embodiments, R2Cis -(CH2)o eNH(R2c1) (such as -NH(R2c1) and -(CH2)I-6NH(R2C1)). In some embodiments, R2Cis -(CH2)I 5N(R2c1)(R2c2). In some embodiments, R2Cis -N(R2C1)(R2C2). In some embodiments, R2Cis -(CH2)„, C(O)N(R2c1)(R2c2) (such as -C(O)N(R2c1)(R2c2) and -(CH2)I6C(O)N(R2C1)(R2C2)).

[0156] In embodiments of any one of the above, each R2c1and R2c2are independently H or C1-C3 alkyl. In some embodiments, R2c1is H. In some embodiments, R2c1is C1-C3 alkyl. In some embodiments, R2c1is Ci alkyl. In some embodiments, R2c1is C2 alkyl. In some embodiments, R2c1is C3 alkyl. In some embodiments, R2c2is H. In some embodiments, R2c2is C1-C3 alkyl. In some embodiments, R2c2is Ci alkyl. In some embodiments, R2c2is C2 alkyl. In some embodiments, R2c2is C3 alkyl.

[0157] In some embodiments, R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cio aryl, 3- to 8-membered heterocycloalkyl, and 5- to 9-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0158] In some embodiments, ring B is C4-C8 cycloalkyl. In some embodiments, ring B is C4 cycloalkyl. In some embodiments, ring B is C5 cycloalkyl. In some embodiments, ring B is C„ cycloalkyl. In some embodiments, ring B is C7 cycloalkyl. In some embodiments, ring B is Cs cycloalkyl. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0159] In some embodiments, ring B is Ce-Cioaryl. In some embodiments, ring B is Cearyl. In some embodiments, ring B is Criaryl. In some embodiments, ring B is Cs aryl. In some embodiments, ring B is C9 aryl. In some embodiments, ring B is C10 aryl. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0160] In some embodiments, ring B is a 3- to 8-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 3 -membered heterocycloalkyl having 1 or 2 heteroatoms which are N or O. In some embodiments, ring B is a 4-membered heterocycloalkyl having 1 or 2 heteroatoms which are N or O. In some embodiments, ring B is a 5 -membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 6-Attorney Ref: 41827-65010 (044WO) membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is a 7-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In some embodiments, ring B is an 8-membered heterocycloalkyl having 1, 2, or 3 heteroatoms which are N or O. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0161] In some embodiments, ring B is a 5- to 9-membered heteroaryl. In some embodiments, ring B is a 5 -membered heteroaryl. In some embodiments, ring B is a 6-membered heteroaryl. In some embodiments, ring B is a 7-membered heteroaryl. In some embodiments, ring B is an 8-membered heteroaryl. In some embodiments, ring B is a 9-membered heteroaryl. In further embodiments, wherein ring B is independently substituted with 0, 1, or 2 R5.

[0162] In some embodiments, R4is H.

[0163] In embodiments of any one of the above, each R5is independently selected from -C2-C6 alkyl, -(CH2)0OH (such as -OH and -(CH2)I6OH), -(CH2)o6CO2H (such as -CO2H and -(CH2)I6CO2H), -(CH2)O^R5AC02H (such as -R5ACO2H and -(CH2)I eR5ACO2H), -(CH2)o 6CO2Ci-Ce alkyl (such as -CO2C1-C6alkyl and -(CH2)I^CO2CI-C6alkyl), -(CH2)0^R5ACO2CI-C6alkyl (such as -R5ACO2CI-C6alkyl and -(CH2)!6R5ACO2CI-C6alkyl), -(CH2)0.6NH2(such as -NH2and -(CH2)I6NH2), -(CH2)„. NHC C, alkyl (such as -NHCi-Ce alkyl and -(CH2)I eNHCi-Ce alkyl), -(CH2)0 6NHR5ACH2OH (such as -NHR5ACH2OH and -(CH2),, NHR 'CH2OH). -(CH2)„, NHR 'CO2H (such as -NHR5ACO2H and -(CH2)I6NHR5ACO2H), -(CH2)O.6NH(CH2)1.6S03H (such as -NH(CH2)1 6SO3H and -(CH2)1-6NH(CH2)1.6SO3H), -(CH2)O.6SH (such as -SH and -(CH2)I^SH), -(CH2)0.6SR5A(such as -SR5Aand -(CH2)I, SRA). -(CH2)06SO3H (such as -SO3H and -(CH2)I6SO3H), -(CH2)0 6SO2NH2(such as -SO2NH2and -(CH2)I „SO2NH2). -(CH2)„ „SO2NHCI-C„ alkyl (such as -SO2NHCI-C6alkyl and -(CH,), „SO2NHCI-C„ alkyl), -(CH2)0.6NH(CH2)i.6OP(O)(OH)2(such as -NH(CH2)i.6OP(O)(OH)2and -(CH2)I6NH(CH2)i.6OP(O)(OH)2), -(CH2)O.6NH(CH2)I.4OP(0)(OH)(OCI-C6 alkyl) (such as - NH(CH2)i.4OP(O)(OH)(OCi-C6alkyl) and -(CH2)I45NH(CH2)I.4OP(O)(OH)(OCI-C6alkyl)), -(CH2)0.6NH(CH2)I.6OP(O)(H)(OH) (such as -NH(CH2)i.6OP(O)(H)(OH) and -(CH2)I6NH(CH2)i.6OP(O)(H)(OH)), -(CH2)„ „P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I^P(O)(OH)2), -(CH2)O 6P(O)(OCI-C6alkyl)2(such as -P(O)(OCi-C6alkyl)2and -(CH2)I 6P(O)(OCi-C6alkyl)2),-(CH2)0-6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)I6OP(O)(OH)2), -(CH2)06OP(O)(OH)(OCI-C6alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I6OP(O)(OH)(OCI-C6alkyl)), -(CH2)0^OP(O)(OCI-C6alkyl)2(such as -OP(O)(OCi-C6alkyl)2and -(CH2)I6OP(O)(OCi-C6alkyl)2), -(CH2)0 6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)^OP(O)(H)(OH)), C4-C8cycloalkyl, -CH2-(C3-C8cycloalkyl), Cs-C8fused bicyclic cycloalkyl, -CH2-(C5-C8fused bicyclic cycloalkyl), C6-C12spirocyclyl, Ce-Cioaryl, -CH2-(Ce-Cio aryl), 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9-membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, -CH2-(7- to 12-membered bicyclic heterocycloalkyl), 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl, and -CH2-(5- to 10-membered heteroaryl), wherein each of the -C2-Ce alkyl, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cio aryl, 5- to 9-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.Attorney Ref: 41827-65010 (044WO)

[0164] In some embodiments, R5is -C2-C6 alkyl. In some embodiments, R5is -(CH2)o eOH (such as -OH and -(CH2)i-eOH). In some embodiments, R5is -(CH2)o 6CO2H (such as -CO2H and -(CH2) 1 C O2H). In some embodiments, R5is -(CH2)o^R5AC02H (such as -R5ACO2H and -(CH2)I eR5ACO2H). In some embodiments, R5is -(CH2)o 6CO2C1-C6 alkyl (such as -CO2C1-C6 alkyl and -(CH2)1–6CO2C1-C6alkyl). In some embodiments, R5is -(CH2) ) nRAC02Ci-C,, alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1–6R5ACO2C1-C6alkyl). In some embodiments, R5is -(CH2)0–6NH2(such as -NH2 and -(CH2)1–6NH2). In some embodiments, R5is -(CH2)u. NHC’i-C,, alkyl (such as -NHCi-Ce alkyl and -(CH2)1–6NHC1-C6alkyl). In some embodiments, R5is -(CH2)0–6NHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)1–6NHR5ACH2OH). In some embodiments, R5is -(CH:),) „NHR CO2H (such as -NHR5ACO2H and -(CH2)I „NHR 'CO2H). In some embodiments, R5is -(CH2)o-6NH(CH2)i 6S03H (such as -NH(CH2)1–6SO3H and -(CH2)I „NH(CH2)I.„SO3H). In some embodiments, R5is -(CH2)0-6SH (such as -SH and -(CH2)I „SH). In some embodiments, R5is -(CH2)0-6SR5A(such as -SR5Aand -(CH2)I-6SR5A). In some embodiments, R5is -(CH2)o 6SO3H (such as -SO3H and -(CH2) 1.. SO^H), In some embodiments, R5is -(CH2)u 3SO2NH2 (such as -SO2NH2 and -(CH2)I 6SO2NH2). In some embodiments, R5is -(CH2)o 6SO2NHC1-C6 alkyl (such as -SO2NHC1-C6 alkyl and -(CH2) 1 3SO2NHC1-C, alkyl). In some embodiments, R5is -(CH2)o 6NH(CH2)i-eOP(O)(OH)2 (such as -NH(CH2)i-eOP(O)(OH)2 and -(CH2)I 6NH(CH2)I.6OP(O)(OH)2). In some embodiments, R5is -(CH2)o 6NH(CH2)i-4OP(O)(OH)(OCi-Ce alkyl) (such as - NH(CH2)I.4OP(O)(OH)(OCI-C6 alkyl) and -(CH2)I^NH(CH2)I.4OP(O)(OH)(OCI-C6 alkyl)). In some embodiments, R5is -(CH2)o 6NH(CH2)i-eOP(O)(H)(OH) (such as -NH(CH2)i-eOP(O)(H)(OH) and -(C H:) 1,, N H(C H:) 1 _<,0 P(O)(H)(OH) ). In some embodiments, R5is -(CH2)o eP(O)(OH)2 (such as -P(O)(OH)2 and -(CH2)I eP(O)(OH)2). In some embodiments, R5is -(CH2)o 6P(O)(OCi-Ce alkyl)2 (such as -P(O)(OCi-Ce alkyl)2 and -(CH2)I 6P(O)(OCi-Ce alkyl^). In some embodiments, R5is -(CH2)0–6OP(O)(OH)2(such as -OP(O)(OH)2 and -(CH:)! „OP(O)(OH)2). In some embodiments, R5is -(CH2)o6OP(O)(OH)(OCI-C6alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I6OP(O)(OH)(OCI-C6alkyl)). In some embodiments, R5is -(CH2)o 6OP(O)(OCi-Ce alkyl)2 (such as -OP(O)(OCi-Ce alkyl)2 and -(CH2)I.1OP(O)(OCi-C„ alkyl)2). In some embodiments, R5is -(CH2)0–6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)I., OP(O)(H)(OH)). In some embodiments, R5is C4-C8 cycloalkyl. In some embodiments, R5is -CH2-(C3-Cs cycloalkyl). In some embodiments, R5is C5-C8fused bicyclic cycloalkyl. In some embodiments, R5is -CH2-(C5-Cs fused bicyclic cycloalkyl). In some embodiments, R5is C6-C12 spirocyclyl. In some embodiments, R5is Ce-Cioaryl. In some embodiments, R5is -CH2-(Ce-Cioaryl). In some embodiments, R5is 5- to 9-membered heterocycloalkyl. In some embodiments, R5is -CH2-(3- to 9-membered heterocycloalkyl). In some embodiments, R5is 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is -CH2-(7- to 12-membered bicyclic heterocycloalkyl). In some embodiments, R5is 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is 5- to 10-membered heteroaryl. In further embodiments, wherein each of the -C2-C6 alkyl, C3-C8 cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.Attorney Ref: 41827-65010 (044WO)

[0165] In some embodiments, R5is -C2-C6 alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, R5is C4 alkyl. In some embodiments, R5is C5 alkyl. In some embodiments, R5is G, alkyl. In further embodiments, wherein -C2-C6 alkyl is independently substituted with 0, 1, or 2 R5B.

[0166] In some embodiments, R5is G-G cycloalkyl. In some embodiments, R5is C3 cycloalkyl. In some embodiments, R5is C4 cycloalkyl. In some embodiments, R5is C5 cycloalkyl. In some embodiments, R5is G, cycloalkyl. In some embodiments, R5is C7 cycloalkyl. In some embodiments, R5is G cycloalkyl. In further embodiments, wherein C3-C8 cycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0167] In some embodiments, R5is C5-C8 fused bicyclic cycloalkyl. In some embodiments, R5is C5 fused bicyclic cycloalkyl. In some embodiments, R5is Ce fused bicyclic cycloalkyl. In some embodiments, R5is C7 fused bicyclic cycloalkyl. In some embodiments, R5is C8fused bicyclic cycloalkyl. In further embodiments, wherein C5-C8fused bicyclic cycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0168] In some embodiments, R5is G-G2 spirocyclyl. In some embodiments, R5is C6spirocyclyl. In some embodiments, R5is G spirocyclyl. In some embodiments, R5is G spirocyclyl. In some embodiments, R5is spirocyclyl. In some embodiments, R5is Go spirocyclyl. In some embodiments, R5is Ci 1 spirocyclyl. In some embodiments, R5is C12 spirocyclyl. In further embodiments, wherein G-C12 spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0169] In some embodiments, R5is G-Goaryl. In some embodiments, R5is Garyl. In some embodiments, R5is Garyl. In some embodiments, R5is aryl. In some embodiments, R5is aryl. In some embodiments, R5is Go aryl. In further embodiments, wherein G-Goaryl is independently substituted with 0, 1, or 2 R5B.

[0170] In some embodiments, R5is a 5- to 9-membered heterocycloalkyl. In some embodiments, R5is a 5-membered heterocycloalkyl. In some embodiments, R5is a 6-membered heterocycloalkyl. In some embodiments, R5is a 7-membered heterocycloalkyl. In some embodiments, R5is an 8-membered heterocycloalkyl. In some embodiments, R5is a 9-membered heterocycloalkyl. In further embodiments, wherein the 5- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0171] In some embodiments, R5is a 3- to 9-membered heterocycloalkyl. In some embodiments, R5is a 3-membered heterocycloalkyl. In some embodiments, R5is a 4-membered heterocycloalkyl. In some embodiments, R5is a 5 -membered heterocycloalkyl. In some embodiments, R5is a 6-membered heterocycloalkyl. In some embodiments, R5is a 7-membered heterocycloalkyl. In some embodiments, R5is an 8-membered heterocycloalkyl. In some embodiments, R5is a 9-membered heterocycloalkyl. In further embodiments, wherein the 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0172] In some embodiments, R5is a 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 7-membered bicyclic heterocycloalkyl. In some embodiments, R5is an 8-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 9-membered bicyclicAttorney Ref: 41827-65010 (044WO) heterocycloalkyl. In some embodiments, R5is a 10-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 11-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 12-membered bicyclic heterocycloalkyl. In further embodiments, wherein the 7- to 12-membered bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0173] In some embodiments, R5is a 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is a 6-membered hetero-spirocyclyl. In some embodiments, R5is a 7-membered hetero-spirocyclyl. In some embodiments, R5is an 8-membered hetero-spirocyclyl. In some embodiments, R5is a 9-membered hetero-spirocyclyl. In some embodiments, R5is a 10-membered hetero-spirocyclyl. In some embodiments, R5is a 11 -membered hetero-spirocyclyl. In some embodiments, R5is a 12-membered hetero-spirocyclyl. In further embodiments, wherein the 6- to 12-membered hetero-spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0174] In some embodiments, R5is a 5- to 10-membered heteroaryl. In some embodiments, R5is a 5-membered heteroaryl. In some embodiments, R5is a 6-membered heteroaryl. In some embodiments, R5is a 7-membered heteroaryl. In some embodiments, R5is an 8-membered heteroaryl. In some embodiments, R5is a 9-membered heteroaryl. In some embodiments, R5is a 10-membered heteroaryl. In further embodiments, wherein the 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0175] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0176] In some embodiments, ring A is selected from:

[0178] In some embodiments, ring A is selected from:Attorney Ref: 41827-65010 (044WO)

[0179] In some embodiments, ring A isIn some embodiments, ring A is\ ^-NHT,A• In some embodiments, ring A is. In some embodiments, ring A isIn some embodiments, ring A isIn some embodiments, ring A isNH. In some embodiments, ring A is

[0180] In some embodiments, ring A is selected from:HIn some embodiments, ring A is

[0182] In some embodiments, R1is H and R2is selected from:Attorney Ref: 41827-65010 (044WO)

[0184] In some embodiments, R1is H and R2is In some embodiments, R1is H and R2is. In some embodiments, R1is H and

[0185] In some embodiments, R1is H and R2is selected from:

[0187] In some embodiments, R1is H and R2isV In some embodiments, R1is H and R2isNH2. In some embodiments, R1is H and R2isNH2. In some embodiments, R1is H and R2is. In some embodiments, R1is H and R2is. In some embodiments, R1is H and R2isNH2. In some embodiments, R1Attorney Ref: 41827-65010 (044WO)is H and R2isH*N?. In some embodiments,R1is H and R2isNHz. In some embodiments,R1is H and R2is. In some embodiments, R1is H and R2isN - R5

[0188] In some embodiments, R1is H; R2is; ring B is; and, R5is - (CH2)3 OH.

[0189] In some embodiments, R1and R2, together with the atoms they are attached to, form a 5 - to 7-membered heterocycloalkyl substituted with 0, 1, or 2 R2Cand R5is -CH,.

[0190] In some embodiments, R1and R2, together with the atoms they are attached to, form:R2C, or (R2C)2

[0191] In some embodiments, R1and R2, together with the atoms they are attached to, form. In some embodiments, R1and R2, together with the atoms they are attached to,form Rzu. Insome embodiments, R1and R2, together with the atoms they are attached to, form>2. In some,oembodiments, R1and R2, together with the atoms they are attached to, form

[0192] In some embodiments, X1is NCR1Aand X2is C. In further embodiments, R1Ais H, C1-C3 alkyl, or C1-C3 haloalkyl.

[0193] In some embodiments, X1is CR1Aand X2is N. In further embodiments, R1Ais H, C1-C3 alkyl, or C1-C3 haloalkyl.Attorney Ref: 41827-65010 (044WO)wherein:R2B,R2C ^-1,R5BR5CR6ag defined asjn Formula(I);R1is H or Ci-Ce alkyl;R2is selected from Ci-Cg alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)0eOR2A, -C(O)R2A, -(CH2)0-6CO2R2A-(CH2)0-6OC(O)R2A-NO2, -CN, -N3, -(CH2)0-6N(R2A)(R2B) -(CH2)0-6C(O)N(R2A)(R2B) -(CH2)O-6SR2A, and ring A;ring A is selected from C3-Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 8-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C;ring B is a 3- to 8-membered heterocycloalkyl;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)0-eOH, -(CH2)OA50CI-C6 alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0A5CO2H; andR5is selected from -C2-C6alkyl, -(CH2)0 6OH, -(CH2)0A5CO2H, -(CH2)0A5R5ACO2H, -(CH2)O 6CO2CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0.6NH2, -(CH2)0-6NHC1-C6alkyl, -(CH2)0 6NHR5ACH2OH, - (CH2)„, NHRAACO2H. -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)0-6NH(CH2)1-6OP(O)(OH)2, -(CH2)0-6P(O)(OH)2, -(CH2)OA5P(0)(OCI-C6 alkyl)2, -(CH2)0A5OP(O)(OH)2, -(CH2)0A5OP(O)(OH)(OCI-C6 alkyl), -(CH2)06OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -C2-Ce alkyl, C -C’s fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0195] In some embodiments, R2is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, -(CH2)0 6OR2A(such as -OR2Aand -(CH2), 0 R ). -C(O)R2A, -(CH2)„, CO2R2A(such as - CO2R2Aand -(CH2)I6CO2R2A), -(CH2)0A5OC(O)R2A(such as -OC(O)R2Aand -(CH2)I, OC(O)R2A). -NO2,Attorney Ref: 41827-65010 (044WO) -CN, -N3, -(CH2)O-6N(R2A)(R2B) (such as -N(R2A)(R2B) and -(CH2)I., N(R2A)(R21')). -(CH2)„6C(O)N(R2A)(R2B) (such as -C(O)N(R2A)(R2B) and -(CH2)I „C(O)N(R2)(R21')). -(CH2)o.6SR2A(such as -SR2Aand-(CH2)i.eSR2A), and ring A.

[0196] In some embodiments, R2is Ci-Ce alkyl. In some embodiments, R2is Ci-Ce haloalkyl. In some embodiments, R2is C2-Ce alkenyl. In some embodiments, R2is C2-Ce alkynyl. In some embodiments, R2is -(CH2)U „OR2(such as -OR2Aand -(CH2)I eOR2A). In some embodiments, R2is -C(O)R2A. In some embodiments, R2is -(CH2)o eCO2R2A(such as -CO2R2Aand -(CH2)I eCO2R2A). In some embodiments, R2is -(CH2)u., OC(O)R2(such as -OC(O)R2Aand -(CH2)I „OC(O)R2). In some embodiments, R2is -NO2. In some embodiments, R2is -CN. In some embodiments, R2is -N3. In some embodiments, R2is -(CH2)o6N(R2A)(R2B) (such as -N(R2A)(R2B) and -(C H2) 1 „N(R2)(R21)). In some embodiments, R2is -(CH2)06C(O)N(R2A)(R2B) (such as -C(O)N(R2A)(R2B) and -(CH2)I, C(O)N(R2)( R21)). In some embodiments, R2is -(CH2)0-6SR2A(such as -SR2Aand -(CH2)I.6SR2A). In some embodiments, R2is ring A.

[0197] In some embodiments, ring A is selected from C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C,,-Ciu aryl, 3- to 8-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0198] In some embodiments, ring A is Cs-Cs cycloalkyl. In some embodiments, ring A is C3 cycloalkyl. In some embodiments, ring A is C4 cycloalkyl. In some embodiments, ring A is C5 cycloalkyl. In some embodiments, ring A is C„ cycloalkyl. In some embodiments, ring A is C7 cycloalkyl. In some embodiments, ring A is Cs cycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0199] In some embodiments, ring A is C5-C8fused bicyclic cycloalkyl. In some embodiments, ring A is C5 fused bicyclic cycloalkyl. In some embodiments, ring A is C„ fused bicyclic cycloalkyl. In some embodiments, ring A is C7 fused bicyclic cycloalkyl. In some embodiments, ring A is Cs fused bicyclic cycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0200] In some embodiments, ring A is Ce-Cioaryl. In some embodiments, ring A is Cearyl. In some embodiments, ring A is C7aryl. In some embodiments, ring A is Cs aryl. In some embodiments, ring A is C9 aryl. In some embodiments, ring A is C10 aryl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0201] In some embodiments, ring A is a 3- to 8-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 3 -membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 4-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 5 -membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 6-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is a 7-membered heterocycloalkyl having one or more nitrogen atoms. In some embodiments, ring A is an 8-membered heterocycloalkyl having one or more nitrogen atoms. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.Attorney Ref: 41827-65010 (044WO)

[0202] In some embodiments, ring A is a 4- to 9-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 4-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 5-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 6-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 7-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is an 8-membered fused bicyclic heterocycloalkyl. In some embodiments, ring A is a 9-membered fused bicyclic heterocycloalkyl. In further embodiments, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C.

[0203] In some embodiments, R3is ring B, wherein ring B is 3- to 8-membered heterocycloalkyl.

[0204] In some embodiments, R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH:),) OH (such as -OH and -(CH2) i OH). -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH2)I eOCi-Ce alkyl), -C(O)H, -C(O)Ci-Ce alkyl, and -(CH:),), CO: H (such as -CO2H and -(CH:): 6CO2H).

[0205] In some embodiments, R4is H. In some embodiments, R4is Ci-Ce alkyl. In some embodiments, R4is Ci-Ce haloalkyl. In some embodiments, R4is halogen. In some embodiments, R4is -(CH:),) OH (such as -OH and -(CH:)i, OH). In some embodiments, R4is -(CH2)o eOCi-Ce alkyl (such as -OCi-Ce alkyl and -(CH:): eOCi-Ce alkyl). In some embodiments, R4is -C(O)H. In some embodiments, R4is -C(O)Ci-Ce alkyl. In some embodiments, R4is -(CH:),), CO: H (such as -CO2H and -(CH2) 1, CO: H).

[0206] In embodiments of any one of the above, each R5is independently selected from -C2-C6 alkyl, -(CH2)0-6OH (such as -OH and -(CH2)1-6OH), -(CH2)0-6CO2H (such as -CO2H and -(CH2)1-6CO2H), -(CH2)U, R CO2H (such as -R5ACO2H and -(CH2)I 6R5ACO3H), -(CH2)o 6CO2C1-C6 alkyl (such as -CO2Ci-C6alkyl and -(CH2)I^CO2CI-C6alkyl), -(CH2)O^R5AC02CI-C6 alkyl (such as -R5ACO2CI-C6alkyl and -(CH2)I6R5ACO2CI-C6alkyl), -(CH2)0-6NH2(such as -NH2and -(CH2)1-6NH2), -(CH2)„. NHC C, alkyl (such as -NHCi-Ce alkyl and -(CH2)I-6NHCI-C6 alkyl), -(CH2)0-6NHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)1-6NHR5ACH2OH), -(CH2)o^NHR5AC02H (such as -NHR5ACO2H and -(CH2)I6NHR5ACO2H), -(CH2)O-6NH(CH2)I.6S03H (such as -NH(CH2)i 6SO3H and -(CH2)I 6NH(CH2)i 6SO3H), -(CH2)0-6NH(CH2)i-60P(0)(OH)2(such as -NH(CH2)I.6OP(O)(OH)2and -(CH2)I^NH(CH2)I.6OP(O)(OH)2), -(CH2)O6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I^P(O)(OH)2), -(CH2)o6P(O)(OCi-C6alkyl)2(such as -P(O)(OCi-C6alkyl)2and -(CH2)I6P(O)(OCi-C6alkyl)2).-(CH2)„,. OP(O)(OH)2(siich as -OP(O)(OH)2and -(CH2)I6OP(O)(OH)2), -(CH2)„ „OP(O)(OH)(OCI-C.. alkyl) (such as -OP(O)(OH)(OCI-C6alkyl) and -(CH2)I6OP(O)(OH)(OCI-C6alkyl)), -(CH2)o6OP(O)(OCi-C6alkyl)2(such as -OP(O)(OCi-C6alkyl): and -(CH:): 6OP(O)(OCi-Ce alkyl):), -(CH:),) „OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH:)i „OP(O)(H)(OH)). C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -C2-C6 alkyl, C -C’s fused bicyclic cycloalkyl, Cg-Ci: spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0207] In some embodiments, R5is -C2-C6 alkyl. In some embodiments, R5is -(CH:)o eOH (such as -OH and -(CH:)i eOH). In some embodiments, R5is -(CH:)o 6CO2H (such as -CO2H and -(CH:)i, CO: H). InAttorney Ref: 41827-65010 (044WO)some embodiments, R5is -(CH2)0–6R5ACO2H (such as -R5ACO2H and -(CH2)1–6R5ACO2H). In some embodiments, R5is -(CH2)0–6CO2C1-C6alkyl (such as -CO2C1-C6 alkyl and -(CH2)1–6CO2C1-C6alkyl). In some embodiments, R5is -(CH2)0–6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1–6R5ACO2C1-C6alkyl). In some embodiments, R5is -(CH2)0–6NH2(such as -NH2 and -(CH2)1–6NH2). In some embodiments, R5is -(CH2)0–6NHC1-C6alkyl (such as -NHCi-Ce alkyl and -(CH2)1–6NHC1-C6alkyl). In some embodiments, R5is -(CH2)0–6NHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)1–6NHR5ACH2OH). In some embodiments, R5is -(CH2)0–6NHR5ACO2H (such as -NHR5ACO2H and -(CH2)1–6NHR5ACO2H). In some embodiments, R5is -(CH2)0–6NH(CH2)1–6SO3H (such as -NH(CH2)1–6SO3H and -(CH2)1–6NH(CH2)1–6SO3H). In some embodiments, R5is -(CH2)0–6NH(CH2)1–6OP(O)(OH)2(such as -NH(CH2)1–6OP(O)(OH)2and -(CH2)1–6NH(CH2)1–6OP(O)(OH)2). In some embodiments, R5is -(CH2)0–6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I 6P(O)(OH)2). In some embodiments, R5is -(CH2)o 6P(O)(OCi-Ce alkyl)2(such as -P(O)(OCi-Ce alkyl)2and -(CH2)I 6P(O)(OCi-Ce alkyl)2). In some embodiments, R5is -(CH2)0–6OP(O)(OH)2(such as -OP(O)(OH)2 and -(CH2)1–6OP(O)(OH)2). In some embodiments, R5is -(CH2)0–6OP(O)(OH)(OC1-C6alkyl) (such as -OP(O)(OH)(OCi-Ce alkyl) and -(CH2)1–6OP(O)(OH)(OC1-C6alkyl)). In some embodiments, R5is -(CH2)0–6OP(O)(OC1-C6alkyl)2(such as -OP(O)(OCi-C6alkyl)2 and -(CH2)1–6OP(O)(OC1-C6alkyl)2. In some embodiments, R5is -(CH2)0–6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)1–6OP(O)(H)(OH)). In some embodiments, R5is C5-C8fused bicyclic cycloalkyl. In some embodiments, R5is C6-C12 spirocyclyl. In some embodiments, R5is 5- to 9-membered heterocycloalkyl. In some embodiments, R5is 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is 5- to 10-membered heteroaryl. In further embodiments, wherein each of the -C2-C6 alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0208] In some embodiments, R5is -C2-C6 alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, R5is C4 alkyl. In some embodiments, R5is C5 alkyl. In some embodiments, R5is C6alkyl. In further embodiments, wherein R5is independently substituted with 0, 1, or 2 R5B.

[0209] In some embodiments, R5is C5-C8fused bicyclic cycloalkyl. In some embodiments, R5is C5 fused bicyclic cycloalkyl. In some embodiments, R5is C6fused bicyclic cycloalkyl. In some embodiments, R5is C7 fused bicyclic cycloalkyl. In some embodiments, R5is C8fused bicyclic cycloalkyl. In further embodiments, wherein -C2-C6 alkyl is independently substituted with 0, 1, or 2 R5B.

[0210] In some embodiments, R5is C6-C12 spirocyclyl. In some embodiments, R5is C6spirocyclyl. In some embodiments, R5is C7 spirocyclyl. In some embodiments, R5is C8spirocyclyl. In some embodiments, R5is C9 spirocyclyl. In some embodiments, R5is C10 spirocyclyl. In some embodiments, R5is Ci 1 spirocyclyl. In some embodiments, R5is C12 spirocyclyl. In further embodiments, wherein C6-C12spirocyclyl is independently substituted with 0, 1, or 2 R5B.Attorney Ref: 41827-65010 (044WO)

[0211] In some embodiments, R5is a 5- to 9-membered heterocycloalkyl. In some embodiments, R5is a 5-membered heterocycloalkyl. In some embodiments, R5is a 6-membered heterocycloalkyl. In some embodiments, R5is a 7-membered heterocycloalkyl. In some embodiments, R5is an 8-membered heterocycloalkyl. In some embodiments, R5is a 9-membered heterocycloalkyl. In further embodiments, wherein the 5- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0212] In some embodiments, R5is a 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 7-membered bicyclic heterocycloalkyl. In some embodiments, R5is an 8-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 9-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 10-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 11-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 12-membered bicyclic heterocycloalkyl. In further embodiments, wherein the 7- to 12-membered bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0213] In some embodiments, R5is a 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is a 6-membered hetero-spirocyclyl. In some embodiments, R5is a 7-membered hetero-spirocyclyl. In some embodiments, R5is an 8-membered hetero-spirocyclyl. In some embodiments, R5is a 9-membered hetero-spirocyclyl. In some embodiments, R5is a 10-membered hetero-spirocyclyl. In some embodiments, R5is a 11 -membered hetero-spirocyclyl. In some embodiments, R5is a 12-membered hetero-spirocyclyl. In further embodiments, wherein the 6- to 12-membered hetero-spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0214] In some embodiments, R5is a 5- to 10-membered heteroaryl. In some embodiments, R5is a 5-membered heteroaryl. In some embodiments, R5is a 6-membered heteroaryl. In some embodiments, R5is a 7-membered heteroaryl. In some embodiments, R5is an 8-membered heteroaryl. In some embodiments, R5is a 9-membered heteroaryl. In some embodiments, R5is a 10-membered heteroaryl. In further embodiments, wherein the 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0215] In some embodiments, R5is selected from:n / vvw AA / VWAttorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)R5is *. In some embodiments, R5is *. In some embodiments, R5is. In some embodiments, R5is *. In some embodiments, R5isIn some embodiments, R5is. In some embodiments, R5is. In some embodiments,R5is. In some embodiments,R5is *. In some embodiments, R5isNH2_ HN - In some embodiments, R5is. In some embodiments, R5is HN - NH / . In some embodiments, R5is *. In some embodiments, R5isAttorney Ref: 41827-65010 (044WO)embodiments, R5is. In some embodiments, R5isembodiments, R5is. In some embodiments, R5isIn some embodiments, R5isIn some embodiments, R5is In some embodiments, R5isAttorney Ref: 41827-65010 (044WO)In some embodiments, R5is In some embodiments, R5is. In some embodiments,. In some embodiments, R5isembodiments, R5is. In some embodiments,R5is In some embodiments, R5isIn some embodiments, R5is In some embodiments, R5is. In some embodiments, R5is. In some embodiments, R5is. In some embodiments, R5is. In some embodiments,R5isAttorney Ref: 41827-65010 (044WO) some embodiments, R5is embodiments, R5isembodiments, R5is In some embodiments, R5isAttorney Ref: 41827-65010 (044WO)embodiments, R5isembodiments, R5is embodiments, R5isAttorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)\. In some embodiments, R5is

[0217] In some embodiments, the compound of Formula (I) is represented by Formula (I-b-1):(I-b-1), wherein:R1, R2, R2A, R2B, ring A, R2C, R2c1, R2c2, X1, R1A, X2, R5A, R5B, R5C, and R5Dare as defined as in Formula (I);R5is selected from -C2-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H. -(CH2)0-6R5ACO2H, -(CH2)0 6CO2Ci-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0.6NH2, -(CH2)0-6NHC1-C6alkyl, -(CH2)0 6NHR5ACH2OH, -(CH2)0-6NHR5ACO2H, -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)0-6NH(CH2)1-6OP(O)(OH)2, -(CH2)0-6P(O)(OH)2, -(CH2)0-6P(O)(OC1-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9-membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl, and -CH2-(5- to 10-membered heteroaryl), wherein each of the C2-Ce alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.Attorney Ref: 41827-65010 (044WO)

[0218] In embodiments of any one of the above, each R5is independently selected from -C2-C6 alkyl, -(CH2)0-6OH (such as -OH and -(CH2)1-6OH), -(CH2)0-6CO2H (such as -CO2H and -(CH2)1-6CO2H), -(CH2)0-6R5ACO2H (such as -R5ACO2H and -(CH2)1-6R5ACO2H), -(CH2)0-6CO2C1-C6alkyl (such as -CO2C1-C6alkyl and -(CH2)1-6CO2C1-C6alkyl), -(CH2)0-6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1-6R5ACO2C1-C6alkyl), -(CH2)0-6NH2(such as -NH2and -(CH2)1-6NH2), -(CH2)0-6NHC1-C6alkyl (such as -NHCi-Ce alkyl and -(CH2)I eNHCi-Ce alkyl), -(CH2)0-6NHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)1-6NHR5ACH2OH), -(CH2)0-6NHR5ACO2H (such as -NHR5ACO2H and -(CH2)1-6NHR5ACO2H), -(CH2)0-6NH(CH2)1-6SO3H (such as -NH(CH2)1-6SO3H and -(CH2)1-6NH(CH2)1-6SO3H), -(CH2)0-6NH(CH2)1-6OP(O)(OH)2(such as -NH(CH2)1-6OP(O)(OH)2and -(CH2)1-6NH(CH2)1-6OP(O)(OH)2), -(CH2)0-6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)1-6P(O)(OH)2), -(CH2)0-6P(O)(OC1-C6alkyl)2(such as -P(O)(OC1-C6alkyl)2and -(CH2)1-6P(O)(OC1-C6alkyl)2),-(CH2)0-6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)1-6OP(O)(OH)2), -(CH2)0-6OP(O)(OH)(OC1-C6alkyl) (such as -OP(O)(OH)(OC1-C6alkyl) and -(CH2)1-6OP(O)(OH)(OC1-C6alkyl)), -(CH2)0-6OP(O)(OC1-C6alkyl)2(such as -OP(O)(OC1-C6alkyl)2and -(CH2)1-6OP(O)(OC1-C6alkyl)2), -(CH2)H „OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)1–6OP(O)(H)(OH)). C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9-membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl, and -CH2-(5- to 10-membered heteroaryl), wherein each of the -C2-Ce alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0219] In some embodiments, R5is -C2-Ce alkyl. In some embodiments, R5is -(CH2)o eOH (such as -OH and -(CH2)I-6OH). In some embodiments, R5is -(CH2)0-6CO2H (such as -CO2H and -(CH2) 1 „CO2H). In some embodiments, R5is -(CH2)u „RACO2H (such as -R5ACO2H and -(CH2)I 6R5ACO2H). In some embodiments, R5is -(CH2)0-6CO2C1-C6alkyl (such as -CO2C1-C6alkyl and -(CH2)1-6CO2C1-C6alkyl). In some embodiments, R5is -(CH2)0-6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1-6R5ACO2C1-C6alkyl). In some embodiments, R5is -(CH2)0-6NH2(such as -NH2and -(CH2)I eNH2). In some embodiments, R5is -(CH2)0-6NHC1-C6alkyl (such as -NHC1-C6alkyl and -(CH2)1-6NHC1-C6alkyl). In some embodiments, R5is -(CH2)0 6NHR5ACH2OH (such as -NHR5ACH2OH and -(CH2)I eNHR5ACH2OH). In some embodiments, R5is -(CH2)0-6NHR5ACO2H (such as -NHR5ACO2H and -(CH2)1-6NHR5ACO2H). In some embodiments, R5is -(CH2)0-6NH(CH2)1-6SO3H (such as -NH(CH2)1-6SO3H and -(CH2)1-6NH(CH2)1-6SO3H). In some embodiments, R5is -(CH2)0-6NH(CH2)1-6OP(O)(OH)2(such as -NH(CH2)1-6OP(O)(OH)2and -(CH2)1-6NH(CH2)1-6OP(O)(OH)2). In some embodiments, R5is -(CH2)0-6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)1-6P(O)(OH)2). In some embodiments, R5is -(CH2)0-6P(O)(OC1-C6alkyl)2(such as -P(O)(OC1-C6alkyl)2and -(CH2)1-6P(O)(OC1-C6alkyl)2). In some embodiments, R5is -(CH2)0-6OP(O)(OH)2(such as -OP(O)(OH)2and -(CH2)1-6OP(O)(OH)2). In some embodiments, R5is -(CH2)0-6OP(O)(OH)(OC1-C6alkyl) (such as -OP(O)(OH)(OC1-C6alkyl) and -(CH2)1-6OP(O)(OH)(OC1-C6alkyl)). In some embodiments, R5is -(CH2)0-6OP(O)(OC1-C6alkyl)2(suchAttorney Ref: 41827-65010 (044WO) as -OP(O)(OC1-C6alkyl)2and -(CH2)1-6OP(O)(OC1-C6alkyl)2). In some embodiments, R5is -(CH2)0-6OP(O)(H)(OH) (such as -OP(O)(H)(OH) and -(CH2)1-6OP(O)(H)(OH)). In some embodiments, R5is C5-C8 fused bicyclic cycloalkyl. In some embodiments, R5is C6-C12 spirocyclyl. In some embodiments, R5is 5- to 9-membered heterocycloalkyl. In some embodiments, R5is -CH2-(3- to 9-membered heterocycloalkyl). In some embodiments, R5is 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is 5- to 10-membered heteroaryl. In some embodiments, R5is -CH2-(5- to 10-membered heteroaryl). In further embodiments, wherein each of the -C2-C6alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0220] In some embodiments, R5is -C2-C6 alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, R5is C4 alkyl. In some embodiments, R5is C5 alkyl. In some embodiments, R5is Ce alkyl. In further embodiments, wherein -C2-C6 alkyl is independently substituted with 0, 1, or 2 R5B.

[0221] In some embodiments, R5is C5-C8fused bicyclic cycloalkyl. In some embodiments, R5is C5fused bicyclic cycloalkyl. In some embodiments, R5is C6fused bicyclic cycloalkyl. In some embodiments, R5is C7fused bicyclic cycloalkyl. In some embodiments, R5is C8fused bicyclic cycloalkyl. In further embodiments, wherein C5-C8fused bicyclic cycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0222] In some embodiments, R5is G-G2 spirocyclyl. In some embodiments, R5is C6spirocyclyl. In some embodiments, R5is G spirocyclyl. In some embodiments, R5is G spirocyclyl. In some embodiments, R5is G spirocyclyl. In some embodiments, R5is Go spirocyclyl. In some embodiments, R5is Ci 1 spirocyclyl. In some embodiments, R5is C12 spirocyclyl. In further embodiments, wherein C6-C12spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0223] In some embodiments, R5is a 5- to 9-membered heterocycloalkyl. In some embodiments, R5is a 5-membered heterocycloalkyl. In some embodiments, R5is a 6-membered heterocycloalkyl. In some embodiments, R5is a 7-membered heterocycloalkyl. In some embodiments, R5is an 8-membered heterocycloalkyl. In some embodiments, R5is a 9-membered heterocycloalkyl. In further embodiments, wherein the 5- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0224] In some embodiments, R5is a 7- to 12-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 7-membered bicyclic heterocycloalkyl. In some embodiments, R5is an 8-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 9-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 10-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 11-membered bicyclic heterocycloalkyl. In some embodiments, R5is a 12-membered bicyclic heterocycloalkyl. In further embodiments, wherein the 7- to 12-membered bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0225] In some embodiments, R5is a 6- to 12-membered hetero-spirocyclyl. In some embodiments, R5is a 6-membered hetero-spirocyclyl. In some embodiments, R5is a 7-membered hetero-spirocyclyl. InAttorney Ref: 41827-65010 (044WO)some embodiments, R5is an 8-membered hetero-spirocyclyl. In some embodiments, R5is a 9-membered hetero-spirocyclyl. In some embodiments, R5is a 10-membered hetero-spirocyclyl. In some embodiments, R5is a 11 -membered hetero-spirocyclyl. In some embodiments, R5is a 12-membered hetero-spirocyclyl. In further embodiments, wherein the 6- to 12-membered hetero-spirocyclyl is independently substituted with 0, 1, or 2 R5B.

[0226] In some embodiments, R5is a 5- to 10-membered heteroaryl. In some embodiments, R5is a 5-membered heteroaryl. In some embodiments, R5is a 6-membered heteroaryl. In some embodiments, R5is a 7-membered heteroaryl. In some embodiments, R5is an 8-membered heteroaryl. In some embodiments, R5is a 9-membered heteroaryl. In some embodiments, R5is a 10-membered heteroaryl. In further embodiments, wherein the 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

[0227] In some embodiments, R5is selected from:Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)

[0228] In some embodiments, R5isIn some embodiments,R5is some embodiments,R5is In some embodiments,R5is embodiments, R5isAttorney Ref: 41827-65010 (044WO)embodiments, R5is embodiments, R5is. In someembodiments, R5is some embodiments, R5is In some embodiments, R5is. In someIn some embodiments, R5is. In some embodiments, R5isIn some embodiments, R5is In some embodiments, R5isAttorney Ref: 41827-65010 (044WO)In some embodiments, R5isIn some embodiments, R5is. In some embodiments, R5is In some embodiments, R5is. In some embodiments, R5isIn some embodiments, R5is embodiments, R5isIn some embodiments, R5isAttorney Ref: 41827-65010 (044WO)OHembodiments,R5is. In some embodiments, R5is. In some embodiments, R5isAttorney Ref: 41827-65010 (044WO)embodiments, R5iso - oembodiments,R5is. In some embodiments, R5isAttorney Ref: 41827-65010 (044WO) embodiments, R5isAttorney Ref: 41827-65010 (044WO)

[0229] In some embodiments, the compound of Formula (I) is represented by Formula (I-b-2):wherein:R1, R2, R2A, R2B, ring A, R2C, R2c1, R2c2, X1, R1A, X2, and R5Bare as defined as in Formula (I);R5is selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CH:),) CCFH. and -(CH2) ). CO2C1-C,, alkyl.

[0230] In embodiments of any one of the above, each R5is independently selected from -Ci-Cg alkyl, -(CPF) ) OH (such as -OH and -(CH2)I eOH), -(CH2)o 6CO2H (such as -CO2H and -(CH2)I 6CO2H), and -Attorney Ref: 41827-65010 (044WO) (CH2) ). CO2C1-C,, alkyl (such as -CO2C1-C6 alkyl and -(CH2)I eCCFCi-Ce alkyl), wherein -Ci-Ce alkyl is independently substituted with 0, 1, or 2 R5B.

[0231] In some embodiments, R5is -Ci-Ce alkyl. In some embodiments, R5is -(CH2)o eOH (such as -OH and -(CH2)i-eOH). In some embodiments, R5is -(CH2)o 6CO2H (such as -CO2H and -(CH2) 1 C O2H). In some embodiments, R5is -(CH2) ). CO2C1-C,, alkyl (such as -CO2C1-C6 alkyl and -(CH2)I 6CO2C1-C6 alkyl). In further embodiments, wherein -Ci-Ce alkyl is independently substituted with 0, 1, or 2 R5B.

[0232] In some embodiments, R5is -Ci-Ce alkyl. In some embodiments, R5is Ci alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, R5is C4 alkyl. In some embodiments, R5is C5 alkyl. In some embodiments, R5is C, alkyl. In further embodiments, wherein -Ci-Ce alkyl is independently substituted with 0, 1, or 2 R5B.

[0233] In some embodiments, R5isor. In some embodiments, R5

[0234] In some embodiments, the compound of Formula (I) is represented by Formula (I-b-3):wherein:R1, R2, R2A, R2B, ring A, R2C, R2c1, R2c2, and R1Aare as defined as in Formula (I);X1is NCR1A;X2is C; andR5Band R5Bare independently selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CPFf 45CO2H, -(CH2)o6CO2Ci-C6alkyl, -(CH2)O-6NH2, and -(CH2)u. NHC’i-C,, alkyl.

[0235] In some embodiments, X1is NCR1A. In some embodiments, R1Ais selected from H, C1.3 alkyl, and C 1.3 haloalky I.

[0236] In some embodiments, X2is C.Attorney Ref: 41827-65010 (044WO)

[0237] In some embodiments, each R5Band R5Bare independently selected from -Ci-Ce alkyl, -(CH2)0-6OH (such as -OH and -(CH2)I6OH), -(CH2)o6CO2H(such as -CO2H and -(CH2)I6CO2H), -(CH2)06CO2Ci-Ce alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I „CO2Ci-C„ alkyl), -(CH2)0-6NH2(such as -NH2and -(CH2)I-6NH2), and -(CH2),)„NHCi-C„ alkyl (such as -NHCi-Ce alkyl and -(CH2)I eNHCi-Ce alkyl).

[0238] In some embodiments, R5Bis -Ci-Ce alkyl. In some embodiments, R5Bis -(CH2)0-eOH (such as -OH and -(CH2)I eOH). In some embodiments, R5Bis -(CH2),)„CO2H (such as -CO2H and -(CH2)I eCO2H). In some embodiments, R5Bis -(CH2)O-6C02CI-C6 alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I 6CO2Ci-Ce alkyl). In some embodiments, R5Bis -(CH2)0-6NH2(such as -NH2and -(CH2)I „NH2). In some embodiments, R5Bis -(CH2)u. NHC’i-C,, alkyl (such as -NHCi-Ce alkyl and -(CH2)I eNHCi-Ce alkyl).

[0239] In some embodiments, R5Bis -Ci-Ce alkyl. In some embodiments, R5Bis -(CRf „OH (such as -OH and -(CH2)I eOH). In some embodiments, R5Bis -(CRf „CO2H (such as -CO2H and -(CH2)I eCO2H). In some embodiments, R5Bis -(CH2)0-6C02Ci-Ce alkyl (such as -CO2Ci-Ce alkyl and -(CH2)I eCO2Ci-Ce alkyl). In some embodiments, R5Bis -(CH2)0-eNH2(such as -NH2and -(CH2)I eNH2). In some embodiments, R5Bis -(CH2)0-6NHC1-C6alkyl (such as -NHC1-C6alkyl and -(CH2)1-6NHC1-C6alkyl).

[0240] In some embodiments, R5Band R5Bare independently selected from:OH O OO OIn some embodiments, R5Bis. In some embodiments, R5Bis. In someembodiments, R. In some embodiments, R5Bis0. In someembodiments, R5Bis. In some embodiments, R5BisAttorney Ref: 41827-65010 (044WO)OH OH

[0241] In some embodiments,R5Bis. In some embodiments,R5Bis O InO Osome embodiments, R5Bis°. In some embodiments, R5Bis O. In some NH2HNembodiments, R5Bis. In some embodiments, R5Bis

[0242] In some embodiments, the compound of Formula (I) is represented by Formula (I-c):wherein:R1, R2, R2A, R2B, ring A, R2C, R2c1, R2c2, X1, R1A, X2, R3, ring B, R5A, R5B, R5C, and R5Dare as defined as in Formula (I);R6is selected from H, -Ci-C6alkyl,-(CH2)o^OH, -(CH2)o6CO2H, -(CH2)o6R5ACO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)O6R5ACO2Ci-C6alkyl, -(CH2)o6P(O)(OH)2, -(CH2)o6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;R6is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)0-eC02H, -(CH2)o 6R5ACO2H, -(CH2)o6CO2Ci-C6alkyl, -(CH2)o6R5ACO2Ci-C6alkyl, -(CH2)o^P(0)(OH)2, -(CH2)o6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Y is O or NH; andm is 1 or 2.

[0243] In some embodiments, m is 1; R6is selected from H, -Ci-Ce alkyl, -(CH2)o OH. -(CH2)0-6CO2H, -(CH2)1), R CO2H. -(CH2)O 6CO2C1-C6 alkyl, -(CH2)0^R5ACO2CI-C6 alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)0Attorney Ref: 41827-65010 (044WO) 6P(O)(OCi-Ce alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B; and R6is selected from deuterium, -Ci-C6alkyl, -(CH2)0-6OH, -(CH2)o6CO2H, -(CH2)0 6R5ACO2H, -(CH2)0 6CO2Ci-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0eP(O)(OH)2, -(CH2)06P(O)(OCi-Ce alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B. In some embodiments, m is 1; R6is selected from H, -Ci-Ce alkyl, -(C H2), OH. -(CH2)0-6CO2H, -(CH2)O6R5ACO2H, -(CH2)O^C02CI-C6 alkyl, -(CH2)06R5ACO2CI-C6 alkyl, -(CH2)0-6P(O)(OH)2, -(CH2)0-6P(O)(OCI-C6 alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B; and R6is deuterium.

[0244] In some embodiments, m is 1; and R6is selected from H, -Ci-Cg alkyl, -(CH2)0 6OH, -(CH2)06CO2H, -(CH2)0-6R5ACO2H, -(CH2)O6CO2C1-C6alkyl, -(CH2)0^R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)H „P(O)(OC’i -C„ alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Cg alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0245] In some embodiments, m is 2; R6is selected from H, -Ci-Ce alkyl, -(CH2)u „OH. -(CH2)u „CO2H. -(CH2)0-6R5ACO2H, -(CH2)O 6CO2CI-C6alkyl, -(CH2)0^R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)06P(O)(OCi-Ce alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B; and R6is (R6)o (i.e., null).

[0246] In embodiments of any one of the above, each R6is independently selected from H, -Ci-Ce alkyl, -(CH2)0-6OH (such as -OH and -(CH2)1-6OH), -(CH2)0-6CO2H (such as -CO2H and -(CH2)1-6CO2H), -(CH2)0-6R5ACO2H (such as -R5ACO2H and -(CH2)1-6R5ACO2H), -(CH2)0-6CO2C1-C6alkyl (such as -CO2C1-C6alkyl and -(CH2)1-6CO2C1-C6alkyl), -(CH2)0-6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1-6R5ACO2C1-C6alkyl), -(CH2)0-6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)1-6P(O)(OH)2), -(CH2)0-6P(O)(OC1-C6alkyl)2(such as -P(O)(OCi-Ce alkyl)2and -(CH2)I 6P(O)(OCi-Ce alkyl)2), and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B; and each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0 6OH (such as -OH and -(CH2)I „OH). -(CH2)0-6CO2H (such as -CO2H and -(CH2)1-6CO2H), -(CH2)O6R5ACO2H (such as -R5ACO2H and -(CH2)I6R5ACO2H), -(CH2)0^CO2CI-C6alkyl (such as -CO2Ci-C6alkyl and -(CH2)I^CO2CI-C6alkyl), -(CH2)0-6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1-6R5ACO2C1-C6alkyl), -(CH2)0-6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)I6P(O)(OH)2), -(CH2)O 6P(O)(OCI-C6alkyl)2(such as -P(O)(OCi-C6alkyl)2and -(CH2)I6P(O)(OCi-C6alkyl)2), and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0247] In some embodiments, R6is H. In some embodiments, R6is deuterium. In some embodiments, R6or R6is -Ci-Ce alkyl. In some embodiments, R6'or R6''is -(CH2)0-6OH (such as -OH and -(CH2)I eOH). In some embodiments, R6'or R6''is -(CH2)0-6CO2H (such as -CO2H and -(CH2)1-6CO2H). In some embodiments, R6'or R6''is -(CH2)0-6R5ACO2H (such as -R5ACO2H and -(CH2)I eR5ACO2H). In someAttorney Ref: 41827-65010 (044WO) embodiments, R6'or R6''is -(CH2)0-6CO2C1-C6alkyl (such as -CO2C1-C6alkyl and -(CH2)1-6CO2C1-C6alkyl). In some embodiments, R6'or R6''is -(CH2)0-6R5ACO2C1-C6alkyl (such as -R5ACO2C1-C6alkyl and -(CH2)1-6R5ACO2C1-C6alkyl). In some embodiments, R6'or R6''is -(CH2)0-6P(O)(OH)2(such as -P(O)(OH)2and -(CH2)1-6P(O)(OH)2). In some embodiments, R6'or R6''is -(CH2)0-6P(O)(OC1-C6alkyl)2(such as -P(O)(OC1-C6alkyl)2and -(CH2)1-6P(O)(OC1-C6alkyl)2). In some embodiments, R6or R6is 4-to 6-membered heterocycloalkyl. In further embodiments, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0248] In some embodiments, R6or R6is -Ci-Cg alkyl. In some embodiments, R6or R6is Ci alkyl. In some embodiments, R6is C2 alkyl. In some embodiments, R6or R6is C3 alkyl. In some embodiments, R6or R6is C4 alkyl. In some embodiments, R6or R6is C5 alkyl. In some embodiments, R6or R6is Ce alkyl. In further embodiments, wherein -Ci-Cg alkyl is independently substituted with 0, 1, or 2 R5B.

[0249] In some embodiments, R6or R6is a 4- to 6-membered heterocycloalkyl. In some embodiments, R6or R6is a 4-membered heterocycloalkyl. In some embodiments, R6or R6is a 5 -membered heterocycloalkyl. In some embodiments, R6or R6is a 6-membered heterocycloalkyl. In further embodiments, wherein the 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B.

[0250] In some embodiments, R6is selected from:Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)

[0252] In some embodiments, R6is. In some embodiments, R6isa - CH3embodiments, R6or R6is. In some embodiments, R6or R6is. In someembodiments,R6or R6. In some embodiments,R6or R6isIn some embodiments,R6or R6is In some embodiments, R6or R6isAttorney Ref: 41827-65010 (044WO)In some embodiments, R6or R6is. In some embodiments,. In some embodiments, R6or R6is embodiments,R6or R6is. In some embodiments, R6or R6isIn some embodiments, R6or R6isAttorney Ref: 41827-65010 (044WO)

[0253] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0254] In some embodiments, R2is selected from G-G cycloalkyl, G-G fused bicyclic cycloalkyl, G-Cio aryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 3- to 9-membered fused bicyclic heterocycloalkyl, wherein each of the G-G cycloalkyl, G-G fused bicyclic cycloalkyl, G-Go aryl, 3- to 9-membered heterocycloalkyl, and 3- to 9-membered fused bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R2C. In some embodiments R1is H, and R2is selected from G-G cycloalkyl, G-G fused bicyclic cycloalkyl, G-Goaryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 3- to 9-membered fused bicyclic heterocycloalkyl, wherein each of the G-Cs cycloalkyl, G-G fused bicyclic cycloalkyl, G-Go aryl, 3- to 9-membered heterocycloalkyl, and 3-to 9-membered fused bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R2C.

[0255] In some embodiments, the compound of Formula (I) is represented by Formula (I-d-1):Attorney Ref: 41827-65010 (044WO)wherein:R2C, R2C1, and R2c2are as defined as in Formula (I);R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;X1is NR1A, wherein R1Ais selected from H, Ci-Ce alkyl and Ci-Ce haloalkyl; R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10- membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0-6CO2H; orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)0-6CO2H, -(CH2)o eR5ACO2H, - (CH2)„.. CO2C-C. alkyl, -(CH2)o 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)o6NHCI-C6alkyl, - (CH2)O^NHR5ACH2OH, -(CH2)O6NHR5ACO2H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6SH, -(CH2)O-6SR5A, -(CH2)O 6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)O-6NH(CH2)I.40P(0)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I.6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)O^OP(0)(OH)(OCI-C6alkyl), -(CH2)o 6OP(O)(OCi-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Cg alkyl, C’s-C’s cycloalkyl, C -C’s fused bicyclic cycloalkyl, Ce-Cn spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Cg alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o6R5ACO2H, -(CH2)O^C02CI-C6 alkyl, -(CH2)o 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)O^N(CI-Attorney Ref: 41827-65010 (044WO) C6alkyl)2, -(CH2)0-6P(O)(OH)2, -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0^OP(O)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a C1-C6aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)0-6OH, -(CH2)0-6NH2, oxo, C3-8cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Cg alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)O6CO2Ci-Ce alkyl, -(CH2)0.6NH2, -(CH2)0eNHCi-Ce alkyl, oxo, C3-Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D; andeach R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)06OP(O)(OH)(OCI-C6alkyl), and -(CH2)0 6OP(O)(H)(OH).

[0256] In some embodiments, the compound of Formula (I) is represented by Formula (I-d-2): / N NR1Oo.bkNH ON,3(I-d-2),wherein:R2C, R2C1, and R2c2are as defined as in Formula (I);R1is H;R2is ring A;Attorney Ref: 41827-65010 (044WO) ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;X1is NR1A, wherein R1Ais selected from H, Ci-Ce alkyl and Ci-Ce haloalkyl; R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10- membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)o^C02H; orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Cg alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, - (CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)o.6NH2, -(CH2)0., NHC|-C„ alkyl, - (CH2)O^NHR5ACH2OH, -(CH2)O6NHR5ACO2H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6SH, -(CH2)O-6SR5A, -(CH2)O 6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O-6NH(CH2)I-6OP(O)(OH)2, -(CH2)O-6NH(CH2)I.40P(0)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I.6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)O^OP(0)(OH)(OCI-C6alkyl), -(CH2)o 6OP(O)(OCi-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, C -Cs fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6NH2, -(CH2)0-6N(C1- C6alkyl)2, -(CH2)O^P(0)(OH)2, -(CH2)O6P(O)(OC1-C6alkyl)2,-(CH2)o6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)O^OP(0)(OCI-C6alkyl)2, -(CH2)o6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)o-eOH, -(CH2)o-eNH2, oxo, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6 alkyl, -(CH2)o-eNH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12 spirocyclyl, Ce-Cioaryl, 3- to 9-memberedAttorney Ref: 41827-65010 (044WO) heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)u. CO2H. -(CH2)o 6CO2Ci-C6alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2)O^OP(0)(OH)2, -(CH2)O6OP(O)(OH)(OCI-C6alkyl), -(CH2)0^OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D; andeach R5Dis independently selected from -Ci-Cg alkyl, halogen, -(CH2)0-60H, -(CH2)o 6CO2H, -(CH2)o6CO2C1-C6alkyl, -(CH2)o.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), and -(CH2)0 6OP(O)(H)(OH).

[0257] In some embodiments, the compound of Formula (I) is represented by Formula (I-e):R11wherein:R2C, R2C1, and R2c2are as defined as in Formula (I);R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)„ A’O2H: orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Cg alkyl, -(CH2)o eOH, -(CH2)u A’CAH. -(CH2)0-6R5ACO2H, -Attorney Ref: 41827-65010 (044WO) (CH2)O^C02CI-C6 alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0 6NHCI-C6alkyl, - (CH2)„, NHR CH2OH. -(CH2)O6NHR5ACO2H, -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)O.6SH, -(CH2)O-6SR5A, -(CH2)O 6SO3H, -(CH2)O6SO2NH2, -(CH2)O^S02NHCI-C6alkyl, -(CH2)0.6NH(CH2)I_6OP(O)(OH)2, -(CH2)0.6NH(CH2)I_4OP(O)(OH)(OCI-C6 alkyl), -(CH2)O-6NH(CH2)I_6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)0^OP(O)(OH)(OCI-C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Cg alkyl, C3-C8cycloalkyl, C -C’s fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o6R5ACO2H, -(CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0^N(CI- C6alkyl)2, -(CH2)0-6P(O)(OH)2, -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0^OP(O)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)0-eOH, -(CH2)0-eNH2, oxo, C3.s cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2Ci-Ce alkyl, -(CH2)0-eNH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Cs cycloalkyl, Ce-Cioaryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)06OP(O)(OH)(OCI-C6alkyl), and -(CH2)0 6OP(O)(H)(OH);Attorney Ref: 41827-65010 (044WO) each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;R10and R11are each hydrogen;X3is CH2, N, or O; andR13is selected from deuterium, -Ci-Cg alkyl, -(CH2)0eOH, -(CH2)0 6CO2H, -(CH2)0 6R5ACO2H, -(CH2)06CO2C1-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, and -(CH2)0-6P(O)(OC1-C6alkyl)2.

[0258] In some embodiments, the compound of Formula (I) is represented by Formula (I-e-1):wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)0-eOH, -(CH2)u. OC’i-C,, alkyl, - C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0-6CO2H; or orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Ce alkyl, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o eR5ACO2H, - (CH2)0^CO2CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0 6NHCI-C6alkyl, - (CH2)„, NHR CH2OH. -(CH2)O6NHR5ACO2H, -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)O.6SH, -(CH2)O-Attorney Ref: 41827-65010 (044WO)6SR5A, -(CH2)O 6SO3H, -(CH2)o 6SO2NH2, -(CH2)O^S02NHCI-C6 alkyl, -(CH2)O.6NH(CH2)I_6OP(O)(OH)2, -(CH2)O.6NH(CH2)I_4OP(0)(OH)(OCI-C6 alkyl), -(CH2)0.6NH(CH2)I_6OP(O)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)O^P(0)(OCI-C6alkyl)2,-(CH2)o6OP(O)(OH)2, - (CH2)0^OP(O)(OH)(OCI-C6alkyl), -(CH2)0 6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 5- to 9- membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, Cs-Cs cycloalkyl, C -C’s fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Cg alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)O6R5ACO2H, -(CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0^N(CI- C6alkyl)2, -(CH2)0-6P(O)(OH)2, -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)O^OP(0)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cioaryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)0-eOH, -(CH2)O-6NH2, OXO, C3-8 cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2Ci-Ce alkyl, -(CH2)0-6NH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12- membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3- C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero- spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5C; each R5Cis independently selected from -Ci-Cg alkyl, halogen, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)06CO2C1-C6alkyl, -(CH2)o.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(H)(OH), C3-C8cycloalkyl, C6-Ci0aryl, 3- to 9- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-C8cycloalkyl, C6-C10aryl, and 3- to 9-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)o.6NH2, -(CH2)0 6SO3H, -(CH2)0-6OP(O)(OH)2, -(CH2)06OP(O)(OH)(OCI-C6alkyl), and -(CH2)0 6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orAttorney Ref: 41827-65010 (044WO) R7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;R10and R11are each hydrogen;X3is CH2or O; and,R13is deuterium.

[0259] In some embodiments, the compound of Formula (I) is represented by Formula (I-f):(I-f),wherein R1, R2, R7, R8, R9, R10, R11, X1, and X2are as defined in Formula (I);R6is selected from H, -Ci-C6alkyl, -(CH2)0 6OH, -(CH2)0 6CO2H, -(CH2)0 6R5ACO2H, -(CH2)0 6CO2Ci- C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)0 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Cg alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;R6is selected from deuterium, -Ci-Cg alkyl, -(CH2)0 6OH, -(CH2)0 6CO2H, -(CH2)0 6R5ACO2H, -(CH2)0 6CO2C1-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)0 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6- membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Y is O or NH; andm is 1 or 2.

[0260] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is any one of the compounds provided in Table 1, Table 2, Table 3, and Table 4.Table 1. Compounds of the present disclosureAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameU / [fN'-Hx kk~o / or)-^N1 Z~~NHO _A\0(2-(4-(5-((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-4-(( 1 S,2S)-2 -methylcyclopropane- 1 - carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)ethyl)phosphonic acid AAR.0™TNU / rN'*H PA / V2 S AN / "~Nethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2-methylcyclopropane-l- carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetate / rnQ7n'ih°3HO72-(4-(5 -((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-4-(( 1 S,2S)-2-methylcyclopropane- 1 - carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)piperazin-l-yl)acetic acidAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameOH^TNu,rN™ PL / Z4V < O O N-— z / O-pZ~~^0diethyl (2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2-methylcyclopropane-l- carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)ethyl)phosphonate / rNU / S5 Z~~NHO __-N-~_zHO-L>T\0((4-(5-((63S,4S, Z)- 11-ethyl- 10, 10-dimethyl-4-(( 1 S,2S)-2 -methylcyclopropane- 1 - carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)methyl)phosphonic acidNU / r- IRAAS z-N6OT\0diethyl ((4-(5-((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-4-(( 1 S,2 S)-2-methylcyclopropane- 1 - carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)methyl)phosphonateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameNQ / 070 N-ZHO0Z^ / o3 -(4-(5 -((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-4-(( 1 S,2S)-2-methylcyclopropane- 1 - carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin-l-yl)propanoic acidIX08 C)_ / O-^ / 0ethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2-methylcyclopropane-l- carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetateNn ' \ No / == / 9^O^NH2Oethyl 2-amino-3 -(4 - (5 -((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-4-(( lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)propanoaAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameNQzLT / A11 ' \ N0 / === / Z~~N10N-ZHO^NH2o2-amino-3 -(4-(5 -((63S,4S, Z)- 11-ethyl- 10, 10-dimethyl-4-(( 1 S,2S)-2-methylcyclopropane- l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin-l-yl)propanoic acidArNiQ11 <^NAethyl 2-(4-(5 -((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-5,7-dioxo-4-((S)-pyrrolidine-3 - carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetateHNO^oJA\12ozethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-5,7-dioxo-4-((R)-pyrrolidine-3- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameHNO.,,°X xx\ZA. O. / V- / ===<^ k-N13ozethyl 2-(4-(5 -((63S,4S, Z)- 11-ethyl- 10,10-dimethyl-5,7-dioxo-4-((S)-piperidine-3- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetateHN / x.OHXJNiQX I X140. 0( / ethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-5,7-dioxo-4-((R)-piperidine-3- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetateHN""kCN-HI kN15ethyl 2-(4-(5 -((63S,4 S, Z)- 11-ethyl- 10, 10-dimethyl-5,7-dioxo-4-(piperidine-4- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameHNCVok kx / O^ k— / ===<kN16c / ethyl 2-(4-(5-((63S,4S, Z)-4-(azetidine-3-carboxamido)-l1-ethyl-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetateHP''-^°2Anu / fN-Hkkko / I kN17 Z~~~Nethyl 2-(4-(5-((63S,4S, Z)-4-((R)-azetidine-2-carboxamido)-l1-ethyl-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetateHN-S^ZAN" kXA kN18k0ethyl 2-(4-(5-((63S,4S, Z)-4-((R)-azetidine-2-carboxamido)-l1-ethyl-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Namer%HOJvS19vPethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-5,7-dioxo-4-((R)-piperidine-2- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetate20 Z~~Nc / ethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-5,7-dioxo-4-((S)-piperidine-2- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetatep QzfN'=HPS~ / ~°Z21o'ethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-5,7-dioxo-4-((R)-pyrrolidine-2- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameAMNkks22 ANozethyl 2-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-5,7-dioxo-4-((S)-pyrrolidine-2- carboxamido)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane- 12-yl)-6-((S)- 1 -methoxyethyl)pyridin-3 -yl)piperazin- 1 - yl)acetate0V XZXAXA CV / AHI23c / ethyl 2-(4-(5-((63S,4S, Z)-4-(( 1 S,2S)-2 -aminocyclopropane- 1 -carboxamido)- I’-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetateNH,A. SAANu,A24 s ANoAethyl 2-(4-(5-((63S,4S, Z)-4-((lR,2R)-2-aminocyclopropane-l-carboxamido)-l1-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameNH2NQz25Z^N( / ethyl 2-(4-(5-((63S,4S, Z)-4-((lR,2S)-2-aminocyclopropane-l-carboxamido)-l1-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetateH2N'--A'Y°2X^A OfN7HS kN26 Z~-NAethyl 2-(4-(5 -((63S,4 S, Z)-4-(( 1 S,2R)-2-aminocyclopropane- 1 -carboxamido)- 11-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetatezj A27ethyl 2-(4-(5-((63S,4S, Z)-4-((lS,2S)-2-aminocyclobutane-l-carboxamido)-l1-ethyl-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6( 1,3)-pyridazinacycloundecaphane- 12-yl)-6-((S) - 1 -methoxyethyl)pyridin-3-yl)piperazin-l-yl)acetateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameNH2X o nXJNXX28 if XNZ~~NXethyl 2-(4-(5-((63S,4S,Z)-4-((1R,2R)-2-aminocyclobutane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateNH2dNXNXX29 I XNXethyl 2-(4-(5-((63S,4S,Z)-4-((1R,2S)-2-aminocyclobutane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateav°JXHsN HN,. [N1AfN' -H 030 s XNXethyl 2-(4-(5-((63S,4S,Z)-4-((1S,2R)-2-aminocyclobutane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateH2NZcJNQ / rN\ / \ zOx / k / ==<31 S ANvOethyl 2-(4-(5 -((63S,4S, Z)-4-(( 1 s,3R)-3 -aminocyclobutane- 1 -carboxamido)- 11-ethyl- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetate■S kk32ethyl 2-(4-(5 -((63S,4S, Z)-4-(( 1 r,3 S)-3 -aminocyclobutane- 1 -carboxamido)- 11-ethyl- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateH2N„'kk° n.NQ / k / k / Ox A”33ethyl 2-(4-(5 -((63S,4S, Z)-4-(( 1 s,4R)-4-aminocyclohexane- 1 -carboxamido)- 11-ethyl- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6( 1,3)-pyridazinacycloundecaphane- 12-yl)-6-((S) - 1 -methoxyethyl)pyridin-3-yl)piperazin-l-yl)acetateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameUWAJrNU.,134 y~^c / ethyl 2-(4-(5 -((63S,4S, Z)-4-(( 1 r,4S)-4-aminocyclohexane- 1 -carboxamido)- 11-ethyl- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateH2NNQ,X / == / 35 J V10, 00ethyl 2-(4-(5-((63S,4S,Z)-4-((1R,3S)-3-aminocyclopentane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateH, NNIk36ethyl 2-(4-(5-((63S,4S,Z)-4-((1R,3R)-3-aminocyclopentane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameH2NVVjnNk kx^o. k— / =k37tk. oethyl 2-(4-(5-((63S,4S, Z)-4-((l S,3R)-3-aminocyclopentane- 1-carboxamido)- I’-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetateH2NCk-° rx38 I kyNtkpethyl 2-(4-(5-((63S,4S,Z)-4-((1S,3S)-3-aminocyclopentane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetate, NH2< ArNQz / ==<39 Jethyl 2-(4-(5-((63S,4S,Z)-4-((1R,2S)-2-aminocyclopentane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameNH2(Lo na™ / NiQ,X o xX40o'ethyl 2-(4-(5-((63S,4S,Z)-4-((1R,2R)-2-aminocyclopentane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateZNH2CLojnOH?^NIQI X41. 0ozethyl 2-(4-(5-((63S,4S, Z)-4-((l S,2R)-2 -aminocyclopentane- 1-carboxamido)- I’-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetateH2NOH3JNiQ / CN'-H42Xethyl 2-(4-(5-((63S,4S,Z)-4-((1S,3S)-3-aminocyclopentane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameNH,0™AN1Q,X TH,43 JZ~-NQethyl 2-(4-(5-((63S,4S, Z)-4-((lR,3R)-3-aminocyclohexane-l-carboxamido)-l1-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l’H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetateNH2OV°AN1QAH T AHA,44 Jozethyl 2-(4-(5-((63S,4S,Z)-4-((1R,3S)-3-aminocyclohexane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateNH2N45 l ANAethyl 2-(4-(5-((63S,4S, Z)-4-((lS,3R)-3-aminocyclohexane-l-carboxamido)-l ’-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l’H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameNH2CVzxNiQkA / OxA46ethyl 2-(4-(5-((63S,4S,Z)-4-((1S,3S)-3-aminocyclohexane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateUk nNQ / Xk A^o^ A— / = / I k 47NA0c / ethyl 2-(4-(5-((63S,4S,Z)-4-((1R,2R)-2-aminocyclohexane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetate.'NH2Uvo jkNIkk^Ax^°x_k\— / = / 48 S ANethyl 2-(4-(5-((63S,4S,Z)-4-((1R,2S)-2-aminocyclohexane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin- 1 -yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameULo jnNiQ / ===<49. Oethyl 2-(4-(5-((63S,4S,Z)-4-((1S,2R)-2-aminocyclohexane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetate.> NH2oH^JNiQCN-H50ethyl 2-(4-(5-((63S,4S, Z)-4-((l S,2S)-2 -aminocyclohexane- 1 -carboxamido)- I’-ethyl- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin- 1 -yl)acetate4^NQz51 oNH2ethyl 3-amino-2-((4-(5-((63S,4S,Z)-11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)methyl)propanoateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameCN-H52 oZ NH23-amino-2-((4-(5-((63S,4S,Z)-11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)methyl)propanoic acidNIQZ=<zf ' ZN53 zN—ZV zNHzHO °2-amino-4-(4-(5-((63S,4S,Z)-11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)butanoic acid<kjNQzX XX ZZf ZN54OV / NH2EtO °ethyl 2-amino-4-(4-(5-((63S,4S,Z)-11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3 -yl)piperazin- 1 -yl)butanoateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NamekrNQ / A rRA55 I kNO HO^ZO2-(4-(5-((63S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetic acidNQ,rN'N" rA x / 56Oo-Z0ethyl 2-(4-(5-((63S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)acetateS VA / " N7'' ^00 / Nk vKI-NF I,057Hethyl 2-((2R)-4-(5-((63S,4S,Z)-11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-2-yl)acetateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Names AA A V00 / N\A Ayy y y580rNfU° HOV / \>H2-((2R)-4-(5-((63S,4S, Z)- 11-ethyl- 10, 10-dimethyl-4-(( 1 S,2S)-2-methylcyclopropane- 1 - carboxamido)-5,7-dioxo-6’,62,63,64,65,66-hexahydro-l’H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin-2-yl)acetic acids AA / A v°r>40( / NA / A AAN1 / HN' / \y yA°A N-NH y ^°A^ / 59AAA > A, AOHethyl 2-((2S)-4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2 -methylcyclopropane- l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l’H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin-2-yl)acetates AA AN7V°0 / N^vA AAy y y60 ° HO' — ' °H2-((2S)-4-(5-((63S,4S, Z)-l ’-ethyl- 10, 10-dimethyl-4-((lS,2S)-2-methylcyclopropane-l- carboxamido)-5,7-dioxo-6’,62,63,64,65,66-hexahydro-l’H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3- yl)piperazin-2-yl)acetic acidJ 's AA J / N 'y°° rN61 hJ-MH,°\- / °H; NJ><<0O-^ethyl 4-(aminomethyl)-l-(5-((63S,4S, Z)-l’-ethyl-10,10-dimethyl-4-((lS,2S)-2-methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l’H-8-oxa-Attorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Name2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)piperidine-4-carboxylateTable 2. Compounds of the present disclosureCpd # Chemical Structure and IUPAC NameJ 1s yA M0o XN / r>-'< < ( r Ny HN"> \ / * O=\ ^-2 " 1N-NH p N62°H2NJ>yoOH4-(aminom ethyl)- 1 -(5-((63S,4S, Z)- 11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperidine-4-carboxylic acidsXy jv v°jJ vN-NH o N63MAH0j><^0ethyl l-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2-methylcyclopropane- l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)-4-(hydroxymethyl)piperidine-4-carboxylateo > N MX 1j CfN-NH o N64Hojy oOH1 -(5-((63S,4S, Z)- 11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)-4-(hydroxymethyl)piperidine-4-carboxylic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name. / =V ) 1s'VA / 'N v°O >=N xY... 1j p> HN' <y C \ / T 'IJ'zo=\nA IN-NH <NX65 AA HNSX^OO-.methyl l-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)-4-((m ethylamino)m ethyl)piperidine-4- carb oxy late / A A JS^A / V V°10A 1N-NH 0 N66<<-Ab HNJX^ OOH1 -(5-((63S,4S, Z)- 11-ethyl - 10,10-dimethyl-4-(( 1 S,2S)-2-methylcyclopropane- 1 - carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)-4-((methylamino)methyl)piperidine-4-carboxylic acid^NH AN — \ J | N 10> —z\ A. NH °=< A- / Y J AN-NH 0 — / **y N^ AA67 ( 070methyl 2-((2R)-l-(3-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)propyl)piperazin-2-yl)acetate •A] )U. / V ANA~NH AN J I N0) — ' \ AYAA k. NH°=< A / J J68 N-NH OAHOA / O O2-((2R)- 1 -(3-(4-(5-((63S,4S, Z)- 11-ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l-yl)propyl)piperazin-2-yl)acetic acid4^-NH Z^N — \ J \ N0*> — ' \ J L., NH °=< " H Jl j r69O-< A °0methyl 2-((2S)-l-(3-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)propyl)piperazin-2-yl)acetate^-NH Z^N J [ N ]0> — ' \ J L 'NHo=< T-7Jl J I"N-NH O-VHOA70 \ ^0002-((2S)-l-(3-(4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l-yl)propyl)piperazin-2-yl)acetic acid^NH / N^|\T N^l<y y ' -A _ / jf TO=\ 1 NTN-NH 0 — O71methyl 2-((2R)-l-(5-((4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l -yl)methyl)pyrimidin-2-yl)piperazin- 2-yl)acetatezXNH / ^Noz5 — ' -A / T TH0\_^A^NH0=\ 1 J / SN-NH.0 — y 072 O '"42-((2R)- 1 -(5-((4-(5-((63S,4S, Z)- 11-ethyl-10,10-dimethyl-4-((1S,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l -yl)methyl)pyrimidin-2-yl)piperazin-2-yl)acetic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namej— NH N^|<r y — ' -A / T TH0\_ e-^ / NHN-NH p — ' A o73 0 -42-((2S)-l-(5-((4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l -yl)methyl)pyrimidin-2-yl)piperazin- 2-yl)acetic acidJ^NH / ^No' y — ' _ / Jj T ^°v e-'x / NHN-NH p — A074 O'"4methyl 2-((2S)-l-(5-((4-(5-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l -yl)methyl)pyrimidin-2-yl)piperazin- 2-yl)acetateIz( I k ho'75 IIx\ N0\ / •*» / / }>HN^(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name76 nX\ No / === / CNU°(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamider -Hi \^ z~oz77Fl ' \ No(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide0ZJNin78nX\ No / Y\ / ’• / / / HN-^Z(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namec / U7CN-H79 IIx\ N(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-9-((S)-l-methoxyethyl)-2,3,4,4a,5,6- hexahydro- lH-pyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazepin- 10-yl)- 10,10-dimethyl- 5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola- 6(1, 3)-pyridazinacy cl oundecaphane-4-yl)-2-methylcy cl opropane-1 -carboxamide7“"80 nX\ Norn(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-9-((S)-l-methoxyethyl)-2,3,4,4a,5,6- hexahydro- lH-pyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazepin- 10-yl)- 10,10-dimethyl- 5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola- 6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideN1Q81 nX\ NoNH HN^ / (lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-2,3,4,4a,5,6- hexahydro- lH-pyrazino[ 1,2-a]pyrido[2,3 -e]pyrazin-9-yl)- 10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameA C, / fN'=HL kA782nX\ NO A / A NHHN—Z(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-2,3,4,4a,5,6- hexahydro- lH-pyrazino[ 1,2-a]pyrido[2,3 -e]pyrazin-9-yl)- 10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideXHOZ83 IIx\ NO 0(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-9-((S)-l-methoxyethyl)-2,3,4,4a,5,6- hexahydro- lH-pyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazepin- 10-yl)- 10,10-dimethyl- 5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola- 6(1, 3)-pyridazinacy cl oundecaphane-4-yl)-2-methylcy cl opropane-1 -carboxamideNIA84 11 ' \ NO / === / (lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-9-((S)-l-methoxyethyl)-2,3,4,4a,5,6- hexahydro- lH-pyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazepin- 10-yl)- 10,10-dimethyl- 5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola- 6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name0™ / NU / r- rUIIx\ N85 rC°N— / 0ethyl 2-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin- 3(4H)-yl)acetateA u / <N'NHvf LfoC2N860 / °HO V- / "" / oz2-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2-methylcyclopropane- l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- 1(5, 3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l-methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)acetic acid AYlUv’-A ZYII ' \ No / == / cp87 N-~Z)O~p\ o'*diethyl (2-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-3 (4H)-yl)ethyl)phosphonateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameo™ / NinCN- LC-C~°ZnoX / \== / NXN\88 N~~Z "7HO-p^HO'^(2-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin- 3(4H)-yl)ethyl)phosphonic acidN1Q.n ' \ No / = / 89 N-Z "^O^NH20ethyl 2-amino-3-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin- 3 (4H)-yl)propanoateXninX XX II ' \ N90 c N-~ZPHO^NH202-amino-3-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-3(4H)-yl)propanoic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameO £A N 0I \„> NH ^-So-,o J N Jy °^° J91i 1 I°\methyl 2-((2R)- 1 -(2-((4aS)-9-((63S,4S, Z)- 11-ethyl- 10, 10-dimethyl-4-(( 1 S,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin- 3(4H)-yl)ethyl)piperazin-2-yl)acetate0 £X.uNH \~SCK, OH J N J922-((2R)- 1 -(2-((4aS)-9-((63S,4S, Z)- 11-ethyl- 10, 10-dimethyl-4-(( 1 S,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin- 3(4H)-yl)ethyl)piperazin-2-yl)acetic acido (\.,«NH / / ~SvoA V0i Srv-093 1 1 LHN\ / if I'" O N^ lmethyl 2-((2R)-l-(3-((4aS)-9-((63S,4S, Z)-l1-ethyl-10,10-dimethyl-4-((lS,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-3(4H)-yl)propyl)piperazin-2-yl)acetateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameo <nA\„> NH V'SJNA OHO£ Y0I A VO94 ZN / X / "Niv£ / 1 I LZN^ANHN\ / : £ L A"'X> 'NZZ|2-((2R)- 1 -(3 -((4aS)-9-((63S,4S, Z)- 11-ethyl- 10, 10-dimethyl-4-(( 1 S,2S)-2- methylcyclopropane-l-carboxamido)-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8- ((S)- 1 -methoxy ethyl)- 1,2,4a,5-tetrahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin- 3(4H)-yl)propyl)piperazin-2-yl)acetic acidO. / \ / / N-N°\_ nH... / °_H™N' M i95Ny / '^ \CO2M6methyl 5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)-2-(piperazin- 1 - yl)pyrimidine-4-carboxylatey.n°zr " r°0. CO Zy - '- ‘96CO2H5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-l1- ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)- thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)-2-(piperazin- 1 -yl)pyrimidine-4-carboxylic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameo. AA / 7 N'NN-A V rHJT\ ’"’ r, — U \- / A °N=(HA r>— ~^. CO2Me / S I97Hrf^X A'N NTZ''1X\ N-^Zmethyl (2S)-l-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylate°y.. O< / J IT V=°0Z-~-ZC°2Hr sHH\ I \NF yzz 198A / A \\ z-T (N^Z— / x(2S)-l-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylic acidV-O°zr°KZ:; O°£°2Mer sH*99 " C" J-}JJ W1methyl (2R)- 1 -(5 -((4-(5 -((63S,4 S, Z)-4-(( 1 r,2R, 3 S)-2, 3 -dimethylcy clopropane- 1 - carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylatevoOz0100rZ rnZ " T(2R)-l-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64, 65,66-hexahydro-l1H-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylic acid0 f \°\ r°HJoMeO2C <7 1 \ N=^HHO i101A A, N A (N 7methyl (2R)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64, 65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylate< / H'N7=OOHO2C 1 \ N=\H102(2R)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64, 65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylic acidvo„ N °z| — I r—r / <^N ° °MeO2C \ u 1 'N=\HVZ- “103HR\ N ' N4 / 1A NA (methyl (2S)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2-yl)piperazine-2-carboxylateAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameyO°zrKX::0°H°2C f i x 'N=\Hv>—104Z yX RZ ‘(2S)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylic acid%..o< / z H-y °0f I Ix n=\Hr \105N-((63S,4 S, Z)- 11-ethyl- 12-(2-((S)-l -methoxy ethyl)-5 -(4-((2-(piperazin- 1 - yl)pyrimidin-5-yl)methyl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-3-methyl-2-oxobutanamide vo°zr " X° °f X JZ 'n==\H1062-cyclopropyl-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2- (piperazin- 1 -yl)pyrimidin-5-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- 1(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide yOozK T° oXX / rvX / 5 H107HN \ / " N 'N_# i(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((6-(piperazin- 1 -yl)pyridin-3 -yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameV-OozH'V°0N-_A"rA- / *NA108Hi N-... ZN'1Cl(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2-(piperazin- 1 -yl)pyrimidin-5-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide O [ \ / V" N'N° r°HJ,o, NA'| — \~ / *NAr \ N=;H109 -a ZN>WS(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2-(4- methylpiperazin- 1 -yl)pyrimidin-5-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamidevo°zrM3r° °f sLAxAH" NA |110(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((6-(4- methylpiperazin- 1 -yl)pyri din-3 -yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamide° f \ / N'N0°\ r°HA,o111 _HHV N^-N AN\1A(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((5-(piperazin-1 -yl)pyrimidin-2-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namedioxo-61, 62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l, 3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide voo ' tfNr° o K- 112\ k \^ 0.3,0^(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((5-(4- methylpiperazin- 1 -yl)pyrimidin-2-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10- dimethyl-5,7 -dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- 1(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideV-O□< / r "k° °fX N=\hv?—113c(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((6-(4- methylpiperazin- 1 -yl)pyridazin-3 -yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10- dimethyl-5,7 -dioxo-61, 62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5, 3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideO / / N-N_o8 r°HT, o_hf- 114 V V-N ri1T \ _ \(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((6-(piperazin- 1 -yl)pyridazin-3 -yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide115Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((5-(4- methylpiperazin- 1 -yl)pyridin-2-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideyO< / y ny0_ tXA AHc116 1 C W1(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((5-(piperazin- 1 -yl)pyridin-2-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5, 7-di oxo- b^b2, b-’Vb^bS-hexahydro-PH-S-oxa^d^-thiazola-l^Syindola-bQ, 3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide / / N'N°\ rHZH0" TOH / VVyvt SHHO^YOHO117H(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(2- (((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)piperazin-l- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane-1-carboxamideO f \Z ' N-N°\ r°HJ / f k Ax / N=\H2 V yyJx / S Y118H° I z- / ^ \H(2S)-3-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)ethyl)amino)-2-hydroxypropanoic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameV-O°zr A0°NA"", — \ / Aikf kA HHA.'OH119 A^!n\ / L zA^kNH(2R)-3-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)ethyl)amino)-2- hydroxypropanoic acidV O°zr A °N -A"" A- / *NA\ A Ax N=\HA— ■9HAAAA / 3ioA Xk A1120 I ]HO < / -■- / NA ( \NH(2S)-4-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l-yl)ethyl)amino)-2-hydroxybutanoic acidyC?°zr "k° °f k X \N=\HA— - ATA Azs [°V^v*10H\Ni121N 1HO \H(3R)-4-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l-yl)ethyl)amino)-3 -hydroxybutanoicacidAttorney Ref: 41827-65010 (044WO)Chemical Structure and IUPAC Name122(3S)-4-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)-l -methoxy ethyl)pyri din-3 -yl)piperazin-l-yl)ethyl)amino)-3 -hydroxybutanoicacidTable 3. Compounds of the present disclosureCpd # Chemical Structure and IUPAC Name123(2R)-3-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)ethyl)amino)-2- hydroxypropanoic acid124✓AO O N H(2R)-3-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -methoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)ethyl)amino)-2-hydroxypropanoic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameo. _,o'" \ / — O HN-N>0HOPo \ 1 / — ( 0Hof1252-((2-(4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)- thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)piperazin-l-yl)ethyl)amino)ethyl dihydrogen phosphateX126 nX\ N0 / N^Az^(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-9-((S)-l-methoxyethyl)-3-methyl- 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-d]pyrido[2,3-b][l,4]oxazepin-10-yl)- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane-1-carboxamideo O127 nX\ Norn(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-9-((S)-l-methoxyethyl)-3-methyl- 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-d]pyrido[2,3-b][l,4]oxazepin-10-yl)- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola- 1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameNU / 128 fl ' \ N.. / O(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-3-methyl- 1,2,3,4,4a,5-hexahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-9-yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideo™ / NYXI X / N.z( ™ I V / -o129 IIx\ Nz°(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-3-methyl- 1,2,3,4,4a,5-hexahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-9-yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- 1(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l- carboxamideO^JNYx130 IIx\ N0O b(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-9-((S)-l-methoxyethyl)-3-methyl- 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-d]pyrido[2,3-b][l,4]oxazepin-10-yl)- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameA-W XOHF O / X O A131 II ' \ NO A=ZO 0(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-9-((S)-l-methoxyethyl)-3-methyl- 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-d]pyrido[2,3-b][l,4]oxazepin-10-yl)- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l- carboxamideo™ / 'N*0,132 II ' \ N0(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-8-((S)-l-methoxyethyl)-3-methyl- 1,2,3,4,4a,5-hexahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-9-yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideNU / i>11x\ N133 0^1 / 0(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-8-((S)-l-methoxyethyl)-3-methyl- 1,2,3,4,4a,5-hexahydropyrazino[ 1,2-d]pyrido[2,3 -b] [ 1,4]oxazin-9-yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- 1(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameo™ZNO / rN'«HjA Zo7nX\ N134 o / = / rC- N~~S(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-8-((S)-l-methoxyethyl)-3-methyl- 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-a]pyrido[2,3-e]pyrazin-9-yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideoH?>fNIlk135 II ' \ NoCV?NH(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-3-methyl- 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-a]pyrido[2,3-e]pyrazin-9-yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideokfNIlk136II ' \ N0< 7 \H(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-9-((S)-l-methoxyethyl)-3-methyl- l,2,3,4,4a,5,6,7-octahydropyrazino[l,2-d]pyrido[2,3-b][l,4]diazepin-10-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameindola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideNiQX137 IIX\ NO O NH(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-9-((S)-l-methoxyethyl)-3-methyl- l,2,3,4,4a,5,6,7-octahydropyrazino[l,2-d]pyrido[2,3-b][l,4]diazepin-10-yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideO^H o"rZ¥yooLH>- 138(4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)- thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)piperazin-l-yl)methyl)pyrimidin-2-yl)piperazin-2- yl)methyl dihydrogen phosphateo r °HT o, SO3HAHr139(4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)- thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methanesulfonic acidAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Name° / V N'N0o r°H / oO OH z-'r r \ J HHN li N— \ *140(4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)- thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)piperazin-l-yl)methyl)pyrimidin-2-yl)piperazin-2- yl)methanesulfonic acid / ° r°HT oz? 0X 0Hr141(l-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)- thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)piperazin-l-yl)methyl)pyrimidin-2-yl)piperazin-2- yl)methanesulfonic acidO _ _ _ / o HN-N142 / N\HN~~X°_ (lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(tetrahydro-2H- pyran-4-yl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide0- °>-O1 1 — o HN-N143, N. J — 4 Js X2-cyclopropyl-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namehexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-oxoacetamide0, _ _ / -0HN-N^x X £ / S- >0I N^ / HN-^144(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(2- morpholinoethyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide 0 z— -x<?" >-O / — 0 HN-N^X N —N= / HN—145(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(l- methylpiperidin-4-yl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideo- yoN VR°HN-N>0jC 1 7 \ / > / ON^ / / N^146(63S,4S, Z)- 1 ^ethyl- 12-(2-((S)- 1 -m ethoxy ethyl)-5-(4-methylpiperazin- 1 - yl)pyri din-3 -yl)- 10,10-dimethyl-4-(4-methyl-2-oxopyrrolidin- 1 -yl)- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-5,7-dioneo- y oN L r~ oHN-NKr T T-A- -Z°x z\ A 1 7 \N > N^ / r~> HN-^147 kz^x / Nxy N-j-yyxs— f \_ / o2-cyclopropyl-N-((63S,4S, Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Name0I0HN-N148{ X / VS(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(7-methyl-7- azaspiro[3.5]nonan-2-yl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide o'HNA=oN== / HN~149 N N s g HJ2-cyclopropyl-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(l- methylpiperidin-4-yl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-oxoacetamideyO< / J, r>=o0f Y r \ N=(H\ 150N(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(3- morpholinopropyl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide0^ y o\ / — o HN-N / >=oX X151N-((63S,4S, Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3-methyl-2-oxobutanamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Nameo- yo1 1 — o HN-Nr~ y=o NJ HK0152(lS,2S)-N-((63S,4S, Z)-l3-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-methylpiperazin- l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8- oxa-2(4,2)-thiazola-l(6,l)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2- methylcyclopropane-1 -carboxamideo' y or°HN-N>oJC JC J \ / / O153 N-Jy — 4 s r^\ J(2R,7aR)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- carboxamide°\ yyohjy of \ r \ NU H154 N \ Z^N 'N_#2-cyclopropyl-N-((63S,4S, Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-((1'-methyl-[1,4'-bipiperidin]-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide o' yo\! — o HN-N / ~ Y=O N^ / HN^°155 / n / A ~V^ys(lS,2S)-N-((63S,4S, Z)-l3-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-methylpiperazin- l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8- oxa-2(4,2)-thiazola-l(6,l)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1 -carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Nameo-' °> nl! — o HN-N156NX2-cyclopropyl-N-((63S,4S, Z)-l3-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66- hexahydro- 11H-8-oxa-2(4,2)-thiazola- 1 (6, 1 )-indola-6( 1,3)- pyridazinacycloundecaphane-4-yl)-2-oxoacetamideo- y ol, — o HN-N^N^XX N^ / HN—1572-cyclobutyl-N-((63S,4S, Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-oxoacetamideo' °>"-Or~ V=oN= / HN— fHO. _N. J N— <7 % — 4 's fS-- 158(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-(3-hydroxypropyl)piperazin-l-yl)-2-((S)- 1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide0- >-OJ-, r°HN-N>oX X159(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-(3-hydroxypropyl)piperazin-l-yl)-2- ((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Nameo" °>-O1 > — o HN-Nr~ \=O160 / N'O'VSj>^ (lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-(2-hydroxyethyl)piperazin-l-yl)-2- ((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide C< \ / - 0 HN-N£ jT r~ k >o161(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(2- (methylamino)ethyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamider>,.. Qr~° HN-i / A rId i I / — < o162(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(3- (methylamino)propyl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide 0 / —.< >" Oi — 0 HN-N / x A I A rNA HN- 163NZ' V / \HNxA '(lS,2S)-N-((63S,4S, Z)-l2-(5-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-l-yl)-2-((S)- l-methoxyethy^pyridin-S-yipP-ethyl-lOJO-dimethyl-SP-dioxo-bXb2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameOt, / — O HN-N^x £ >oJ 1NW HN—164. ^~~~ / / A__ / \HNC?7<; X / V >- ( 1 S,2S)-N-((63S,4S, Z)- 12-(5-(4-(2-azaspiro[3.3 ]heptan-6-yl)piperazin- 1 -yl)-2-((S)- l-methoxyethy^pyridin-S-yl^-P-ethyl-lOJO-dimethyl-SX-dioxoX1^2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide1 / / X-Z °HN'N165H2N( XJHu(lS,2S)-N-((63S,4S, Z)-l2-(5-(4-(6-aminospiro[3.3]heptan-2-yl)piperazin-l-yl)-2- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)- 1 ^ethyl- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide 0 / - \ / — O HN-NN=y HN^°166HN^ [>— *( 1 S,2S)-N-((63S,4S, Z)- 12-(5-(4-(azeti din-3 -yl)piperazin- 1 -yl)-2-((S)- 1 - methoxy ethy^pyridin-S-y^-P-ethyl-lOJO-dimethyl-SX-dioxo-b1^2^3^4^5^6- hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide O _ _.-0 HN~N / b" / ^OJ 1 Vx N^ / HN^°167HNx>(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(piperidin-4- y^piperazin-l-y^pyridin-S-y^-lOJO-dimethyl-SX-dioxo-b1^2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Nameo _ _0rNA r°HN~N168 QvoHNY°HNCJX--> V=== / Y-S(lS,2S)-N-((63S,4S, Z)-l2-(5-(4-(2-azaspiro[3.5]nonan-7-yl)piperazin-l-yl)-2-((S)- l-methoxyethy^pyridin-S-y^-P-ethyl-lOJO-dimethyl-S^-dioxo^1^2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideo- y o\ —ozHN-NN^ P-^ _ / >=Q XjO~XBj w°169(IS, 2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((5, 6,7,8- tetrahydroimidazof 1,2-a]pyrazin-2-yl)methyl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- 1(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l- carboxamide^N^ I^ / — o HN-NHN^X J r r-^°J 1HN^f170 ' Y W 's(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(2-(piperazin-l- yl)pyrimidin-4-yl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide< °>" ON L / — o HN-NN r T JL / r-s \ / — v / ,N'NN / HN-y171 / ^N^X / N-s^y Z A rX^*HN^ _ y(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrazin-3-yl)methyl)piperazin-l-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thi azola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC NameP 1 _ 0 HN-N / =OHO £ L172LM J ^N~£^-^VS(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2-(piperazin-l- yl)pyrimidin-5-yl)methyl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide0, yoo _\ / NuZHN-Nr ^=oo3 / N^ [>^17HN J(lS,2S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((l-(piperidin-4- yl)-lH-pyrazol-4-yl)methyl)piperazin-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide < r~A )'" HCN-N^£ jT >o174 H2N-^N\> / NAhn^( 1 S,2S)-N-((63S,4S, Z)- 12-(5-(4-(2-aminoethyl)piperazin- 1 -yl)-2-((S)- 1 - methoxyethy^pyridin-S-y^-P-ethyl-lOJO-dimethyl-S^-dioxo-bXb2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide 0,,, / — O HN-NH N 11 / P175( 1 S,2S)-N-((63S,4S, Z)- 12-(5-(4-(3 -aminopropyl)piperazin- 1 -yl)-2-((S)- 1 - methoxyethy^pyridin-S-y^-P-ethyl-lOJO-dimethyl-S^-dioxo-bXb2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Nameo'N / — 0 HN-N / x X 1 rr >°176 XM N'XV-4 kxx l>- ( 1 r,2R,3 S)-N-((63S,4S, Z)- 12-(5-(4-(6-aminospiro[3.3 ]heptan-2-yl)piperazin- 1 -yl)- 2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide« °>"" OZ1, — o HN-NN^A / y=°r T / — K, / o177H2NXHN-- N N XN(lS,2S)-N-((63S,4S, Z)-l2-(5-(4-(5-aminopentyl)piperazin-l-yl)-2-((S)-l- methoxyethy^pyridin-S-y^-P-ethyl-lOJO-dimethyl-S^-dioxo-b1^2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamider°>.. QXl rX X°178. N^zZ _ / \\= / [>— (lS,2S)-N-((63S,4S, Z)-l2-(5-(4-(4-aminobutyl)piperazin-l-yl)-2-((S)-l- methoxyethy^pyridin-S-y^-P-ethyl-lOJO-dimethyl-S^-dioxo-b1^2^3^4^5^6- hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamideo- y or°HN’Voif X / \ / \ o179NX / NX / N-X N X^XXXSSr(63S,4S, Z)- 1 ^ethyl- 12-(2-((S)- 1 -m ethoxy ethyl)-5-(4-methylpiperazin- 1 - yl)pyridin-3-yl)-10,10-dimethyl-4-(6-oxo-5-azaspiro[2.4]heptan-5-yl)- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-5,7-dioneAttorney Ref: 41827-65010 (044WO)Cpd # Chemical Structure and IUPAC Namezw< / r— oHN'N\=oMeM kw / y°°2c / Y rrL k J.,n=(hOv N i ryvsf 180N ' JYN->methyl 4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H- 8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6- ((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylate / 2'0 r"°HJT 0co2Me yN=sHk-" 181HrO 'N_Fy^ / 1kz N^z / methyl l-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)piperazine-2-carboxylate0 / — o HN-N71 ' / -AI N^ / HN^1 1 N^z / YniN<182(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-(l- methylpiperidin-4-yl)piperazin- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamidez°y OO oZ HN'N^o^-4 / °HO \ H 1 \ / y IN=\H''i\183r n ' N— < / r NjLNk(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-((2-(4-hydroxypiperidin-l- yl)pyrimidin-5-yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxy ethyl)pyri din-3 -yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namel(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-;-l -carboxamideTable 4. Compounds of the present disclosureCpd # Chemical Structure and IUPAC Name° / J ry°0CO2H V- r rt ll nH1842-((2R)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin- 3-yl)piperazin-l-yl)methyl)pyrimidin-2-yl)piperazin-2-yl)acetic acid yOCO2H < / r / *N-^ °y XX / XxyHf- 185™ Ji yf N-( / 12-((2S)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin- 3-yl)piperazin-l-yl)methyl)pyrimidin-2-yl)piperazin-2-yl)acetic acidc> / A '0 o' HN-NAKy* _ L,oHoy 1HK _186 O N- / VASr yw1( lr,2R,3 S)-N-((63S,4S, Z)- 11-ethyl- l2-(5-(4-((2-(4-(hydroxymethyl)piperidin- 1 - yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name< / J H->00 / OH Nx / ’r-t- £H£~187™ 11 "'f 'N-, M / 1K / N^ (7N< Z^ / \(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-((2-((R)-3-(hydroxymethyl)piperazin-l- yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide 0 [ \ / y N-N0v r°HJT °OH — I—188 -- f X Xx n=\HHR\ N ' \n / / i / N^ ((lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-((2-((S)-3-(hydroxymethyl)piperazin-l- yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide V O OH=°f3ZOHO 0Zr—uH H'NX^°0189 £HHr! L zN-, N-# / "'f1 / N'-ZX 7((2R)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin- 3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methyl dihydrogen phosphate v o°Zr-0 H Voz £XAX x5H?- 190Ht NZ fZN^Z"^X((2S)-4-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin- 3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methyl dihydrogen phosphateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namev o< / rMA° °f X AX N=\H191"€->).,0 W ‘ (lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-((2-((S)-2-(hydroxymethyl)piperazin-l- yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide O I / N'No°\_ rHXT °H° LXAX Hh192. N-^Zx 7(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(5-(4-((2-((R)-2-(hydroxymethyl)piperazin-l- yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3 -yl)- 10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide 0VH v rHA >1 f l 1 'N=\HV— 193HN \NN-C *((2S)-l-(5-((4-(5-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin- 3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methyl dihydrogen phosphate v O°x X A0HNX° O194 ° / n=\ *X. / N-X (X 7((2R)- 1 -(5 -((4-(5 -((63S,4S, Z)-4-(( 1 r,2R,3 S)-2, 3 -dimethylcyclopropane- 1 -carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Namel(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin- 3 -yl)piperazin- 1 -yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methyl dihydrogen phosphate195A XN. 0HN N^, \NA(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-3-((2-(piperazin-l- yl)pyrimidin-5 -yl)methyl)- 1,2, 3, 4, 4a, 5 -hexahydropyrazino [ 1,2-d]pyrido [2,3- b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane- 1 -carboxamideA / AX AH, / =X196 LNHN^AI^NA A(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-8-((S)-l-methoxyethyl)-3-((2-(piperazin-l- yl)pyrimidin-5 -yl)methyl)- 1,2, 3, 4, 4a, 5 -hexahydropyrazino [ 1,2-d]pyrido [2,3- b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane- 1 -carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name0™ / NiQ,197 AA A\\ \(1r,2R,3S)-N-((6³S,4S,Z)-1¹-ethyl-1²-((R)-9-((S)-1-methoxyethyl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-d]pyrido[2,3-b][1,4]oxazepin-10-yl)-10,10-dimethyl-5,7-dioxo-6¹,6²,6³,6⁴,6⁵,6⁶-hexahydro-1¹H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamideA / AOHS<NIQ / A198 A S AHNl <'1 0(1r,2R,3S)-N-((6³S,4S,Z)-1¹-ethyl-1²-((S)-9-((S)-1-methoxyethyl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-d]pyrido[2,3-b][1,4]oxazepin-10-yl)-10,10-dimethyl-5,7-dioxo-6¹,6²,6³,6⁴,6⁵,6⁶-hexahydro-1¹H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamideAH Xjlo / 199 Af AN / -A (A OHOY N-AZ7 / N-^'', / OH(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-3-((2-((S)-3-(hydroxymethyl)piperazin-l-yl)pyrimidin-5-yl)methyl)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5-hexahydropyrazino[l,2-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Named]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro- l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane- 1 -carboxamideJ■KJ " U / 200OH(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-3-((2-((S)-3-(hydroxymethyl)piperazin-l- yl)pyrimidin-5-yl)methyl)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5-hexahydropyrazino[l,2- d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro- l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane- 1 -carboxamide°HAJ O201HN\ _ "I / (OH(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((S)-3-((2-((R)-3-(hydroxymethyl)piperazin-l- yl)pyrimidin-5-yl)methyl)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5-hexahydropyrazino[l,2- d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro- l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane- 1 -carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameI r N< A OI rOi / k A^o. A- / ====(202 / -X A 0A YA -A\" H-^OH(lr,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((R)-3-((2-((R)-3-(hydroxymethyl)piperazin-l- yl)pyrimidin-5-yl)methyl)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5-hexahydropyrazino[l,2- d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro- l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane- 1 -carboxamideAA ANiQ1 \ N— / r AN'^AHv / oV / AA203ZA 0O^Z / OH(2S)-4-(5-(((4aS)-9-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)- l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l-methoxyethyl)-l,2,4a,5- tetrahydropyrazino [1,2 -d]pyrido [2, 3 -b] [ 1,4] oxazin-3 (4H) -yl)methyl)pyrimidin-2- yl)piperazine-2-carboxylic acidr 'AAAXH204 TK,< A 0o^’ NA7OHAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name(2R)-4-(5-(((4aS)-9-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l- methoxyethyl)- 1,2, 4a, 5 -tetrahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-3 (4H)- yl)methyl)pyrimidin-2-yl)piperazine-2 -carboxylic acidnHN, 1v O / ~H2050U°-xHO0H((2S)-4-(5-(((4aS)-9-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l- methoxyethyl)- 1,2, 4a, 5 -tetrahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-3 (4H)- yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methyl dihydrogen phosphatev O) — \ / / ~H1 J. / ll206 ° jL / NOX°HO0H((2R)-4-(5-(((4aS)-9-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l- methoxyethyl)- 1,2, 4a, 5 -tetrahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-3 (4H)-yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methyl dihydrogen phosphateAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NamenHNz / v O / NH1. N-zX\ n [ \ X / 207F0£ JLOH°z'b yF(((2S)-4-(5-(((4aS)-9-((63S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-6¹,6²,6³,6⁴,6⁵,6⁶-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-8-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methanesulfonic acidnHNz / xF iOx / 1 L z208, ° 1 / NZOH°"((((2R)-4-(5-(((4aS)-9-((63S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-6¹,6²,6³,6⁴,6⁵,6⁶-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-12-yl)-8-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)methyl)pyrimidin-2-yl)piperazin-2-yl)methanesulfonic acidAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NamenHNz / NX^T F jr NH NX^XA [ y L / 209 / / X XXoX01 / N0 ™ N.,N, (X 'X 1 J ’'-- HO NX-7 02-((2R)-4-(5-(((4aS)-9-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l- methoxyethyl)- 1,2, 4a, 5 -tetrahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-3 (4H)- yl)methyl)pyrimidin-2-yl)piperazin-2-yl)acetic acidX h„HNZ / NX-,' Q‘NH —7210 IT AX°X0OoHO^N, XN XHO N-XX- 2-((2S)-4-(5-(((4aS)-9-((63S,4S, Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-l2-yl)-8-((S)-l- methoxyethyl)- 1,2, 4a, 5 -tetrahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-3 (4H)- yl)methyl)pyrimidin-2-yl)piperazin-2-yl)acetic acidx ° XHIM,. X M^XX,xA / 1■N nhrx >°z211o X=zXNx°HNX(2R,3S)-N-((64S,4S, Z)-l1-ethyl-l2-((4aS)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-l1H- 8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameozNX rCF3( l / KVZ^N |HN-^ / ' '=\o NKJ,212°irN.H / xh>.(2R,3S)-N-((64S,4S, Z)-l2-((4aS)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-9-yl)- 10,10-dimethyl-5,7-dioxo- 11- (2,2,2-trifluoroethyl)-l’H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamide* H \Nz,„ ( \ J / y=l ' / -oO=Z / \ / N~NHQ213HN N-X7\ _ / N— '(2R, 3S)-N-((64S, 4S, Z)-1 ’-ethyl- l2-((4aS)-8-((S)-l-methoxyethyl)-3-((2-(piperazin-l- yl)pyrimidin-5 -yl)methyl)- 1,2, 3, 4, 4a, 5 -hexahydropyrazino [ 1,2-d]pyrido [2,3- b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-l’H-8-oxa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3- dimethylcyclopropane- 1 -carboxamideozrCF3HN^An|o Nx1214°1:NHvxNVBA.>.(2R,3S)-N-((64S,4S, Z)-l2-((4aS)-8-((S)-l-methoxyethyl)-3-((2-(piperazin-l-yl)pyrimidin- 5-yl)methyl)-l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-l’-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Nameindola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideozHN^ GA 1I U M G215 CHNr> NH 0G H \ A^Z 0 H \]>.(2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2-(piperazin-l- yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)pyridin-3 -yl)- 10,10-dimethyl-5,7-dioxo- 1 'H-8- oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamide ozrCFaHN^Gn / "'N | A-GGN^Z / '216 □A0 NP> NH / ^-Z oA H N4°H>.(2R,3S)-N-((63S,4S, Z)-l2-(2-((S)-l-methoxyethyl)-5-(4-((2-(piperazin-l-yl)pyrimidin-5- yl)methyl)piperazin- 1 -yl)pyridin-3 -yl)- 10,10-dimethyl-5,7-dioxo- 11-(2,2,2-trifluoroethyl)- l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 lheptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamideVN / K217 0^ fNri‘R>« ■KI.^\rS) 0\(lR,2R,3S)-N-((64S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-3-methyl-l,2,3,4,4a,5- hexahydropyrazinofl^-dJpyridoP^-blfl^Joxazin-O-y^-lOJO-dimethyl-S^-dioxo-l’H- 8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameF3C 1N > '■: / fa> S / YM A / NVN / \ L0( \ / ?\(s; / N4§K218 N'JHcY < ii(R) / L / l^\TS) 0\(lR,2R,3S)-N-((64S,4S, Z)-l2-((S)-8-((S)-l-methoxyethyl)-3-methyl-l,2,3,4,4a,5- hexahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-9-yl)- 10,10-dimethyl-5,7-dioxo- 11- (2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamide>-M fas / yVCAAO L219W i* N ”. ° Q^\ps) 0\(lR,2R,3S)-N-((64S,4S, Z)-l1-ethyl-l2-((4aS,5S)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamideN faVN I \° r 9\fSj220 \ / N 7 H c< ((lR,2R,3S)-N-((64S,4S, Z)-12-((4aS,5S)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 lheptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamidefa!>221 0r "‘ N N-.0CN>^\rS) 0\Attorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC Name(lR,2R,3S)-N-((64S,4S, Z)-l1-ethyl-l2-((4aS,5R)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamideJ— N fasfa fa jjo A C AAo222A* N N-. ° QY\ fa0\(lR,2R,3S)-N-((64S,4S, Z)-12-((4aS,5R)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamidefaV-N / J° r oAs; NZA*223 v NJ H cfa ( iN ", I, / r fa o \(lR,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((4aS,5S)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide FsC |r faV-N / K224 NJ H ( L< fa 0 \(lR,2R,3S)-N-((63S,4S, Z)-l2-((4aS,5S)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-l1-(2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameY~N " Y Cfs°;\^n] \ '<o'''•WuA \fs;225\0Q< l(S) 0 \(lR,2R,3S)-N-((63S,4S, Z)-l1-ethyl-l2-((4aS,5R)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide F3C IR / °[J V~N po r C YX0 / W i® J JW226\0CN)< Us}XO \(lR,2R,3S)-N-((63S,4S, Z)-l2-((4aS,5R)-8-((S)-l-methoxyethyl)-3,5-dimethyl- l,2,3,4,4a,5-hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7- dioxo-l1-(2,2,2-trifluoroethyl)-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola- l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l- carboxamideH / A / r-G HN-NYS X x°227 Y v\ / XXJ 1 \ — K N= / 0 / \=A^S(lr,2R,3S)-N-((64S, 4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[l,2-d]pyrido[2,3-b][l,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-l1H- 8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideAttorney Ref: 41827-65010 (044WO) Cpd # Chemical Structure and IUPAC NameHr0 °>~AYX X228 NLY ) >'NXXY < 2 — x N=Z 0 / f YJYV3(lr,2R,3S)-N-((62S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-9-yl)-10,10-dimethyl-5,7-dioxo-1¹H- 8-oxa-63,64-diaza-2(4,2)-thiazola-l(5,3)-indola-6(4,2)- bicyclo[4.1.0]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideA / z-0 HN-NYX X229 XY ) / XXY > 2 — x N=Z oo / A f / Y\Y~Y / S(lr,2R,3S)-N-((61R,65S,66S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-9-yl)- 10,10-dimethyl-5,7-dioxo- 1 ’H- 8-oxa-63,64-diaza-2(4,2)-thiazola-l(5,3)-indola-6(3,5)- bicyclo[4.1.01heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide H IA r’J / z-0 HN-NYX X X°230 ^Y AX / XXY > ) — x N=Y 0o ''' AYY / Y / YY-^8(lr,2R,3S)-N-((61R,62S,66S,4S, Z)-l1-ethyl-l2-((S)-8-((S)-l-methoxyethyl)-l,2,3,4,4a,5- hexahydropyrazino [ 1,2-d]pyrido [2,3 -b] [ 1,4] oxazin-9-yl)- 10,10-dimethyl-5,7-dioxo- 1 ’H- 8-oxa-63,64-diaza-2(4,2)-thiazola-l(5,3)-indola-6(4,2)-bicyclo[4.1.0]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamideAttorney Ref: 41827-65010 (044WO)NHr V-N / 1 ii[ x>-NQr-0 HN-Nr \ A )=oN J> / \'N” xj~ 0A / A0'1 f X= / AxS( 1 r,2R,3 S)-N-((64S,4 S, Z)- 12-(5 -(4-((2-( piperazin- 1 -yl)pyrimidin-5-yl)methyl)piperazin- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3 -yl)- 11-ethyl- 10,10-dimethyl-5,7-dioxo- 1 'H-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane- 4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamideNH J V-N / _ k / / 0 v AA X A0Y YAJ ' ) — \ N=Z oi f \=A^S(lr,2R,3S)-N-((62S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2-(piperazin-l- yl)pyrimidin-5-yl)methyl)piperazin- 1 -yl)pyridin-3-yl)- 10, 10-dimethyl-5,7-dioxo- l'H-8- oxa-63,64-diaza-2(4,2)-thiazola-l(5,3)-indola-6(4,2)- bicyclo[4.1.01heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide NHA \-N / ii0 v AJ",-0 HN-NrA A[ YA / X) — X N=Z 0i ( A=A^S(lr,2R,3S)-N-((61R,65S,66S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(4-((2- (piperazin- 1 -yl)pyrimidin-5 -yl)methyl)piperazin- 1 -yl)pyridin-3 -yl)- 10,10-dimethyl-5,7- dioxo-l1H-8-oxa-63,64-diaza-2(4,2)-thiazola-l(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamideAttorney Ref: 41827-65010 (044WO)NH2 IIx—f \^Nvo1 / -O HN-NA X A0-4-J < 2 — A N=Z 01 ( 2=>^s(lr,2R,3S)-N-((61R,62S,66S,4S, Z)-l1-ethyl-l2-(2-((S)-l-methox...

Claims

Attorney Docket No.: 41827-65010 (044WO) WHAT IS CLAIMED IS:

1. A compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein:- is a single bond or a double bond;R1is H or Ci-Cg alkyl;R2is selected from Ci-Cg alkyl, Ci-Cg haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)o eOR2A, -C(O)R2A, -(CH2)1)„CO2R2. -(C H2),,, OC(O)R2. -NO2, -CN, -N3, -(CH2)1. N( R2)( R21). -(C H2) > „C(O)N(R2)(R2I;). -(CH2)0-6SR2A, and ring A;ring A is selected from C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9- membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C; orR1and R2form, along with the atoms they are attached to, a 5 - to 7- membered heterocycloalkyl substituted with 0, 1, or 2 R2C;each R2Aand R2Bare independently selected from H, Ci-Ce alkyl, -(QDo-eOH, -(QDo eOCi-Ce alkyl, -C(O)H, -C(O)Ci-C6alkyl, -(CH2)o6CO2H, -(CH2)o 6CO2Ci-C6alkyl, and C3-C8cycloalkyl; each R2Cis independently selected from Ci-Ce alkyl, halogen, -(CH2) ) OH. -(CH2)o eOCi-Ce alkyl, oxo, -C(O)H, -C(O)Ci-C6alkyl, -(CH2)0-6CO2H, -(CH2)0^CO2CI-C6alkyl, -NO2, -N3, -(CH2)06NH(R2C1), -(CH2)„, N(R2)(R2c2). -(CH2)O-6C(0)N(R2C1)(R2C2), and C3-C8spirocycloalkyl;each R2c1and R2c2are independently H or Ci-Cg alkyl;X1is NR1Aor CR1A,wherein R1Ais selected from H, Ci-Ce alkyl, and Ci-Ce haloalkyl;X2is N or C;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein ring B is independently substituted with 0, l, or 2 R5;Attorney Ref: 41827-65010 (044WO) R4is selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, -(CH2)o eOH, -(CH2)o „OCi-C„ alkyl, -C(O)H, -C(O)Ci-C6alkyl, and -(CH2)0^CO2H; orR3and R4form, together with the atoms they are attached to, a 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms selected from N, S, and O, and the 8- to 15-membered fused bicyclic or tricyclic heterocyclic ring is independently substituted with 0, 1, 2, or 3 R6;each R5is independently selected from -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)0-6CO2H, -(CH2)o eR5ACO2H, -(CH2)O^C02CI-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)0 6NHCI-C6alkyl, -(CH2)06NHR5ACH2OH, -(CH2)O 6NHR5ACO2H, -(CH2)0.6NH(CH2)1.6SO3H, -(CH2)O.6SH, -(CH2)O.6SR5A, -(CH2)O6SO3H, -(CH2), „SO2NH2. -(CH2)O6SO2NHCI-C6alkyl, -(CH2)0.6NH(CH2)1 6OP(O)(OH)2, -(CH2)0.6NH(CH2)1 4OP(O)(OH)(OCI-C6alkyl), -(CH2)O.6NH(CH2)1 6OP(0)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)0-6P(O)(OC1-C6alkyl)2.-(CH2),)„OP(O)(OH)2. -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C4-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -Ci-Ce alkyl, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3-to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; each R6is independently selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)o6R5ACO2H, -(CH2)O^C02CI-C6 alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6NH2, -(CH2)„.. NfC-C, alkyl)2, -(CH2)0 6P(O)(OH)2, -(CH2)O 6P(O)(OCI-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0^OP(O)(OCI-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), C3-C8cycloalkyl, Ce-Cio aryl, and 3- to 9-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl, C4-C8 cycloalkyl, Ce-Cio aryl, and 5- to 9-membered heterocycloalkyl, is independently substituted with 0, 1, or 2 R5B;R5Ais a Ci -Ce aliphatic alkyl chain optionally substituted with one or more groups selected from halogen, -(CH2)0-6OH, -(CH2)0-6NH2, oxo, C3.s cycloalkyl, and 3- to 9-membered heterocycloalkyl; each R5Bis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2Ci-Ce alkyl, -(CH2)0-6NH2, -(CH2)o eNHCi-Ce alkyl, oxo, C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein each of the C3-Cs cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10- membered heteroaryl is independently substituted with 0, 1, or 2 R5C;each R5Cis independently selected from -Ci-Ce alkyl, halogen, -(CH2)0-eOH, -(CH2)0-6CO2H, -(CH2)o 6CO2C1-C6alkyl, -(CH2)0 6NH2, -(CH2)0 6SO3H, -(CH2)u., OP(O)(OH)2. -(CH2)0 6OP(O)(OH)(OCI-C6alkyl), -(CH2)U., OP(O)(H)(OH). C3-CS cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl,Attorney Ref: 41827-65010 (044WO) and 5- to 10-membered heteroaryl, wherein each of the Cs-Cs cycloalkyl, Ce-Cio aryl, and 3- to 9- membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5D;each R5Dis independently selected from -Ci-Ce alkyl, halogen, -(CH2)o eOH, -(CH2)o 6CO2H, -(ClDo 6CO2Ci-C6alkyl, -(CH2)O-6NH2, -(CH2)O6SO3H, -(CH2),, OP(O)(OH)2. -(CH2)O 6OP(O)(OH)(OCI-C6alkyl), and -(CH2)o6OP(O)(H)(OH);each R7, R8, and R9are hydrogen; orR7and R8form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R9is hydrogen; orR7and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R8is hydrogen; orR8and R9form, along with the atoms they are attached to, a 3 - to 6-membered cycloalkyl, and R7is hydrogen;each R10, R11, and R12are hydrogen; orR12and X1form, along with the atoms they are attached to, a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl, and the 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 R13; and R10and R11are each hydrogen; andR13is selected from deuterium, -Ci-Ce alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, -(ClDo 6CO2C1-C6 alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, and -(CH2)O^P(0)(OCI-C6alkyl)2.

2. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-a):wherein:ring A is selected from Cs-Ce cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl;each R2Cis independently selected from C1-C3 alkyl, halogen, -(CH2)0-6OH, -(CH2)u r,0Ci-C,, alkyl, oxo, -C(O)C1-C6alkyl, -(CH2)0-6CO2H, -(CH2)0^CO2CI-C6alkyl, -(CH2)0 6NH(R2c1), -(CH2)1-5N(R2C1)(R2C2), -N(R2C1)(R2C2), and -(CH2)0 6C(O)N(R2c1)(R2c2);Attorney Ref: 41827-65010 (044WO) each R2C1and R2C2are independently H or C1-C3alkyl;R4is H;R3is ring B, wherein ring B is selected from C4-C8 cycloalkyl, Ce-Cioaryl, 3- to 8-membered heterocycloalkyl, and 5- to 9-membered heteroaryl, wherein ring B is independently substituted with 0, 1, or 2 R5;each R5is independently selected from -C2-C6 alkyl, -(CH2)o eOH, -(CH2)o 6CO2H, -(CH2)o eR5ACO2H, -(CH2)O^C02CI-C6 alkyl, -(CH2)o 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)o6NHCI-C6alkyl, -(CH2)o6NHR5ACH2OH, -(CH2)O 6NHR5ACO2H, -(CH2)O-6NH(CH2)I.6S03H, -(CH2)O-6SH, -(CH2)O.6SR5A, -(CH2)O6SO3H, -(CH2)„.. SO2NH2. -(CH2)0 6SO2NHC1-C6alkyl, -(CH2)0.6NH(CH2)1.6OP(O)(OH)2, -(CH2)0.6NH(CH2)1 4OP(O)(OH)(OCI-C6alkyl), -(CH2)O.6NH(CH2)I.60P(0)(H)(OH), -(CH2)0-6P(O)(OH)2, -(CH2)0-6P(O)(OC1-C6alkyl)2, -(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0 6OP(O)(H)(OH), -C4-C8cycloalkyl, -CH2-(C3-C8cycloalkyl), C5-C8fused bicyclic cycloalkyl, -CH2-(C5-C8fused bicyclic cycloalkyl), C6-C12spirocyclyl, Ce-Cioaryl, -CH2-(Ce-Cio aryl), 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9-membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, -CH2-(7- to 12-membered bicyclic heterocycloalkyl), 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl and -CH2-(5- to 10-membered heteroaryl), wherein each of the -C2-C6 alkyl, C4-C8cycloalkyl, Cs-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, Ce-Cio aryl, 5- to 9-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B; andn is 0, 1, or 2.

3. The compound of claim 1 or 2, wherein ring A is selected from Cs-Ce cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 8-membered fused bicyclic heterocycloalkyl, wherein each R2Cis independently selected from C1-C3 alkyl, halogen, -(CH2)o2OH, -(CH2)u 2OC1-C3 alkyl, and amino.

4. The compound of any one of claims 1 to 3, wherein ring A is selected from:

5. The compound of any one of claims 1 to 3, wherein ring A is selected from:Attorney Ref: 41827-65010 (044WO) 6. The compound of any one of claims 1 to 3, wherein ring A is selected from:

7. The compound of claim 1, wherein R1is H and R2is selected from:

8. The compound of any one of claims 1 to 3, wherein R1is H and R2is selected from:

9. The compound of claim 1, wherein:R1is H;R5is -(CH2)3 6OH.

10. The compound of claim 1, wherein R1and R2, together with the atoms they are attached to, form a 5- to 7- membered heterocycloalkyl substituted with 0, 1, or 2 R2Cand R5is -CH3.

11. The compound of claim 1, wherein R1and R2, together with the atoms they are attached to, form:Attorney Ref: 41827-65010 (044WO)12. The compound of claim 1, wherein R1and R2, together with the atoms they are attached to, form:

13. The compound of any one of claims 1 to 12, wherein X1is NR1Aand X2is C, wherein R1Ais H or C1-C3 alkyl.

14. The compound of any one of claims 1 to 12, wherein X1is CR1Aand X2is N, wherein R1Ais H or C1-C3 alkyl.

15. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-b):wherein:R2is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)0-6OR2A, -C(O)R2A, -(CH2)O^C02R2A, -(CH2)O^OC(0)R2A, -NO2, -CN, -N3, -(CH2)O^N(R2A)(R2B), -(CH2)O^C(0)N(R2A)(R2B), -(CH2)0-6SR2A, and ring A;ring A is selected from C3-C8 cycloalkyl, C5-C8fused bicyclic cycloalkyl, Ce-Cioaryl, 3- to 8-membered heterocycloalkyl having one or more nitrogen atoms, and 4- to 9-membered fused bicyclic heterocycloalkyl, wherein ring A is independently substituted with 0, 1, 2, or 3 R2C;ring B is a 3- to 8-membered heterocycloalkyl; andR5is selected from -C2-C6alkyl, -(CH2)0-6OH, -(CH2)„ A’O2H. -(CH2)o^R5AC02H, -(CH2)o 6CO2Ci-C6alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)0-6NH2, -(CH2)u. NHC’i-C,, alkyl, -(CH2)o6NHR5ACH2OH, -(CH2)O^NHR5AC02H, -(CH2)O-6NH(CH2)I-6S03H, -(CH2)O-6NH(CH2)I-60P(0)(OH)2, -(CH2)O6P(O)(OH)2,Attorney Ref: 41827-65010 (044WO) -(CH2)O^P(0)(OCI-C6alkyl)2, -(CH2)0-6OP(O)(OH)2, -(CH2)„, OP(O)(OH)(OC C. alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl, wherein each of the -C2-Ce alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

16. The compound of claim 15, wherein R5is selected from:Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)17. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-b- 1):(I-b-1)wherein:R5is selected from -C2-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H. -(CH2)0-6R5ACO2H, -(CH2)0 6CO2Ci-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0.6NH2, -(CH2)0-6NHC1-C6alkyl, -(CH2)0 6NHR5ACH2OH, -(CH2)0-6NHR5ACO2H, -(CH2)0-6NH(CH2)1-6SO3H, -(CH2)0-6NH(CH2)1-6OP(O)(OH)2, -(CH2)0-6P(O)(OH)2, -(CH2)0-6P(O)(OC1-C6alkyl)2,-(CH2)0-6OP(O)(OH)2, -(CH2)0-6OP(O)(OH)(OC1-C6alkyl), -(CH2)0-6OP(O)(OCi-C6alkyl)2, -(CH2)0-6OP(O)(H)(OH), C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 5- to 9-membered heterocycloalkyl, -CH2-(3- to 9-membered heterocycloalkyl), 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-membered hetero-spirocyclyl, 5- to 10-membered heteroaryl, and -CH2-(5- to 10-membered heteroaryl), wherein each of the C2-Ce alkyl, C5-C8fused bicyclic cycloalkyl, C6-C12spirocyclyl, 3- to 9-membered heterocycloalkyl, 7- to 12-membered bicyclic heterocycloalkyl, 6- to 12-Attorney Ref: 41827-65010 (044WO) membered hetero-spirocyclyl, and 5- to 10-membered heteroaryl is independently substituted with 0, 1, or 2 R5B.

18. The compound of claim 17, wherein R5is selected from:Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)19. The compound of claim 17 or 18, wherein X1is NR1Aand X2is C.

20. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-b-wherein:R5is selected from -Ci-Ce alkyl, -(QDo-eOH, -(CHf CCTH. and -(CH2) ). CO2C1-C,, alkyl.

21. The compound of claim 20, wherein R5isAttorney Ref: 41827-65010 (044WO) 22. The compound of claim 20 or 21, wherein X1is NR1Aand X2is C.

23. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-b- 3):wherein:X1is NCR1A;X2is C; andR5Band R5Bare independently selected from -Ci-Cg alkyl, -(CH2)0-60H, -(CH2)u ^CO2H, -(CH2)06CO2Ci-C6alkyl, -(CH2)o.6NH2, and -(CH2)„. NHC C, alkyl.

24. The compound of claim 23, wherein R5Band R5Bare independently selected from:

25. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-c):wherein:Attorney Ref: 41827-65010 (044WO) R6'is selected from H, -C1-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)0-6R5ACO2C1-C6alkyl, -(CH2)0-6P(O)(OH)2, -(CH2)0 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;R6''is selected from deuterium, -C1-C6alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)o 6CO2Ci-C6alkyl, -(CH2)0 6R5ACO2CI-C6alkyl, -(CH2)0 6P(O)(OH)2, -(CH2)0 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Y is O or NH; andm is 1 or 2.

26. The compound of claim 25, wherein R6is selected from:Attorney Ref: 41827-65010 (044WO)27. The compound of claim 25 or 26, wherein m is 1, and R6is deuterium.

28. The compound of claim 25 or 26, wherein m is 2.

29. The compound according to claim 25, wherein R1is H, and R2is selected from C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C10aryl, 3- to 9-membered heterocycloalkyl having one or more nitrogen atoms, and 3- to 9-membered fused bicyclic heterocycloalkyl, wherein each of the C3-C8cycloalkyl, C5-C8fused bicyclic cycloalkyl, C6-C10aryl, 3- to 9-membered heterocycloalkyl, and 3- to 9- membered fused bicyclic heterocycloalkyl is independently substituted with 0, 1, or 2 R2C.

30. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-d-wherein:R1is H;Attorney Ref: 41827-65010 (044WO) R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C; and,X1is NR1A, wherein R1Ais selected from H, Ci-Ce alkyl and Ci-Ce haloalkyl.

31. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-d- 2):wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C; and,X1is NR1A, wherein R1Ais selected from H, Ci-Cg alkyl and Ci-Cg haloalkyl.

32. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-e):R11wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;X3is CH2, N, or O; andAttorney Ref: 41827-65010 (044WO) R13is selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, and -(CH2)O^P(0)(OCI-C6alkyl)2.

33. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-e-1):wherein:R1is H;R2is ring A;ring A is C3-C8cycloalkyl substituted with 0, 1, 2, or 3 R2C;X3is CH2or O; andR13is deuterium.

34. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (I-f):(I-f),wherein:R6is selected from H, -Ci-C6alkyl, -(CH2)0-6OH, -(CH2)o6CO2H, -(CH2)o6R5ACO2H, -(CH2)o6CO2Ci- C6alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)0-6P(O)(OH)2, -(CH2)o 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6-membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Attorney Ref: 41827-65010 (044WO) R6is selected from deuterium, -Ci-Ce alkyl, -(CH2)0-6OH, -(CH2)0-6CO2H, -(CH2)0-6R5ACO2H, -(CH2)0-6CO2C1-C6alkyl, -(CH2)O 6R5ACO2CI-C6alkyl, -(CH2)o6P(O)(OH)2, -(CH2)o 6P(O)(OCi-C6alkyl)2, and 4- to 6-membered heterocycloalkyl, wherein each of the -Ci-Ce alkyl and 4- to 6- membered heterocycloalkyl is independently substituted with 0, 1, or 2 R5B;Y is O or NH; andm is 1 or 2.

35. The compound according to claim 1, wherein the compound is selected from:Attorney Ref: 41827-65010 (044WO)y^r\ XNX / X x X < X^ZZ\ \ I ) o / o zzi.X Y. o oZI. i XK< A1° KA1° o □K H XOX y y^ < OCKp < \ / \ / — Z \ _ _ _ _V0 5 ^^xxx4 X f- ^z\"yz> \"■ O XNQ / X rXC } o— / zO'X T\0 5Attorney Ref: 41827-65010 (044WO)oo oxI V'Z 0yz'z"<"" '"' '' ' Ju z y / £ zx / / - / \ 1 / \ _Z. ■ \ / \ 1 ' _ 1 z<eJ O 1 z / N0 o \z. r )\^ ~ vk / I >z> r i0 g x > O0°°w° “ X< O / o O A Z" ' —NZr A Z" ™ ' - > >y v > >ZWVz i t z-o w'zTVznr\°T^ o ' / \= / N rzx<^ )r X <0 N — ' ^O^NH2o 5Attorney Ref: 41827-65010 (044WO)o^N^Q / rN> njv Z" N ozoox xV-z A "" )X5 w\l / \ _ z 'O o 1 Z \ z> >x x0O °< ( O O A A Z Z"" ' - ' —> VzVzT cX I4'" i ^X°°^Oc \n\-=° JH / 4 f i ^l z\\" - oAttorney Ref: 41827-65010 (044WO)o^N|Q<~N o'5O-TN^X r& s 43PX°°' \"o W'\- V^,J °lz / v \ / —0 z _o'5 4 ii.z> \"■• oHoH^ / I X / N., r ^hr \_^ozvOo ~^5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)oxv-z"' )x / \V-z- ^ '>x\ MOA>- ° °Zl\(^ °z"> WVzr>z->",°z•xz < AA FfXM C Y yvo^z oZ' " < <YX'OO°°='^^ou> O \AV',V° J °z z1 i!Y \ / \4 f JZ^z"z\y" \"yoz X<^Noz5Attorney Ref: 41827-65010 (044WO)NH2N, k A / O\A“ / *=<ox1Xz ''"""' ' oz)f iX5 / \K--Z ^ 'NH2O A \z. - >x\oO °-^( O A Z"' ') Xz'o^JNU / CMz' 'X Mk / X / O-x / V / ^\1 0c>5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)H2NNiQ / I X / N., r NH H X kA, O^- / ===(YNoxc> yvz""!r5 \ / _ Z '>x\oO °-^ °( O A Z'" ' - N) X M > wzVH°xCMI rz z\\ V\< p Y / oZi'Y YX°° ° \^^'OeoXc 4n^_Y °z°z1 1 / 4 4 fZ fz\ Y z \"..o^ OAttorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)NH,rPH^A po / o KzP5 NH20-YO2Ao?NQ / PJ' ^ PI X / N, r A °°^ 4^o \cox^ P p ° Jz / 0. 0a 4Z f J AZ>"■°\ 5 NH2O^°JPo^JNiQ / I X / N., r ™ r L pozo °> P5Attorney Ref: 41827-65010 (044WO)<-'\y. NH2ULojnoH? JNCN-HC)5? \ I y o z i w ■ — KO=\y °z / \ / — ■Z. _4 T / / -rx~xy»NH2CLojnoH<>iNiQ / I X / N. r "hr y^ozvPoz^5.> NH2OHP / NiQ / I X / NP r / ~~NV. NJC> ^5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)<£> " xx, I X / N.zr r L / 'o / ^- 0N-y ( o HO-V 0 A ° / 0V ■Z'°" ^ 5 AAX YX CN°° QzY^ TXX-^ N X / N.r r ix o XA / O^ X- z^xVXO ° Z~~N XN^N-y:9 X _ / Wk#J<oo0 57 / ~zo^ °s 7" A / ^ J / O 0NX^Nx ' J'-<^O y rx-^ HN" <> ( X / r XJ / * o=( Z''' / N-NH ^0H0H 5Attorney Ref: 41827-65010 (044WO)36. The compound according to claim 1, wherein the compound is selected from:Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)O. / V V N / 'XO _ _ z^NH / — N — \ J f N N 1 ° y — ' 1 J L 'NH °y oO-{ TN' " A5 AL c^ °OONH / N ^l$T N''^]0A 1 J / °x 1. NH N-NH.0 — \ 0 ol V# 50) / o \ J^Ntl / N7 r VVN^oz5 — ' ~\ 1 Jj THOy_.z^z^Ho=\ 1 / T""*N-NH P — \ °I5j-NH / ^NOZ- ' ^\ _ / Jf JH°V e-^ / NHN-NH p — ' 1 °o-<0-° 5j-NH ON TyVyzN r / ^s'JNZ^V ^^N^iN-^I0 / S f I J " V e^-NHN-NH P — 1 O0-4 -° 5Attorney Ref: 41827-65010 (044WO)OH-TN^QrN^H2JL > OZP1K II ' \ N o o J z °z1 / =<( T X f _N3\ / \ / ^\X^ z z _ _ _ _5 X Vhs j J / ?i \ / ? \o <&> " XPnoX\ N / = / cOHN- / ^ 5Attorney Ref: 41827-65010 (044WO)XNU / rN n- X^5~ / ~°zII ' \ N rOox5 Vv Y* "' _z^XYz' ^y YxX) \ X^Z ' ' / 1o r zO™TO A Z <l' ' -Y x >°WNU / > WYzr UP / 1 / -vM nx- XYx II \ N A10 / \ >= / ° JzO b H IN \ / ^X zXVJ5 ryx^ R Y'z x'.}.,o^Attorney Ref: 41827-65010 (044WO)o^JNIQ, CN'=Hrl> A < )voZ"‘ 1 ) OZ " 11 ' \ N O >= / (A K1° O Z I O o Z J O o HN^> -,,z^_ / 5 \ / =p RJ< - A o z...O\rv ^1 0 l!^ 1 / JO / rN'NH VO-Z'°0HO r 'N_ypoz5Attorney Ref: 41827-65010 (044WO)oxVyoz" > r \ / \ X / / _ Z i / \ X / -Z - °H4>Nr ) / O 1 Z / A^I XN.z( -X >)H-°- ° " i Lx ) V / A- " II ' \ N o / == / r N~Vp / z" 1 / H LC1KHOO=-p^O' Q 5 Wf oXzvIYT \oN1Q / I XN.z( "HXX nX\ N o0 N-~ / -° HO-^"NH*0 5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)\ 1 — o HN-N_ / y=oH / <N^ > N XJbX ^,N=( - ^^N— Z / VS50, _Kc< >"< \ / — 0 HN-NHN I ^ 1 I N J v ' / r~^ \ ° nN N J 1 \ — vN=V HN-X u 5< °>'- ON A! —0 HN-Nr Y rS / X° AN~N NX HN—^ / \ / NX\ — 4 s rs— HN^ _ yN\__ / 5O- °>' OX _ o HN-N N^A^. I y=° HN^^I r T i Y~~ / — <» _^P N Jk / O x / N^yy^s50, yoo _ HN-NN x r A° C I AT ' H<>NAJX ^N-<yxs50A" \ ) AN\AS, / —0HN-NI Jf rX >01Nl / — v0H2N^V / N\A NX~A / XHNA'5Attorney Ref: 41827-65010 (044WO)Jov o“ ’'0 / —} / — y O ° 0 HN-N / x 1 1WUXJ rF O^ T >--,n= / HN~A° / VT ( tyu >- H2N^^ ' / b 5Z.—- z •0>n1, — 0 HN-N ^N^ A^ / >=0 \ Y / — K, / o z.. k 11 / / v / / I CX I O? FH2N X / V / V' N ^Y N Y00\^< y A- “5SY 0co S"\ \ 1 o ) _ r^N\Ys, / — ° HN-N oI 1 FT- / ^° H2N'^V^X / N J r Y-, HNF'>— 5zV Ooz^0 ""'NyoMe°2c / Y rr / ^N-FHNK l zxklbO L / AV'^ / N=( \ H L> _— L^N^N-, OAN- / VVS[l N _ / / \= / 5Attorney Ref: 41827-65010 (044WO)38. The compound according to claim 1, wherein the compound is selected from:Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)NQ I XN.zr n w IxkN / ~N. 0HN N^, \ ).„ / A N~~yOH5<rN'X7,X / HN^AI^N^\OH50™TNQ / r- / -- Al oHO Y^(N^"' / \ O" HN-Z^5Attorney Ref: 41827-65010 (044WO)NIQ1 XN, I A / -, / ~Nv 0H\O" V "-XS" / '< N-^ / OH 5OHA)NX AX0 / k Px^o^ P— / ===<ANz-~\ <Z~NV oHIO-<N’=V / 'N--^'''’ / OH 50™>l O XHk Ax^°x^A T— / K A, Af ' QZ-~\ <Z~t O O^ “v'’ A N-Aj / 1^OH5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Y~N '-r fa° UN / L0r? V F JU rNT A' N N<u-x fa ° \5F3C IIYY 5%5VN / L ° r Ai?Z''*W> Y \fs; J FA (<\Ur; 0Q \5 F3C I •PA Y F: (xAF / F° A \5Attorney Ref: 41827-65010 (044WO)r fc.. if'5 F3C 1 >-N p SAAA / N VN / L p r vi AAA A / iW -- A tu H A r: =( )V j\jsj0\5^-x ) '"’p S / ^T ^AAXAN VN / K ° r Ai? \fs; y N-^AW V NJ H ( L.iRj zHA n y \ 70N'N'-. Af f(S) 0 \5F3C 1•A J'T ks. jA? ~f(S) 'O \5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)N^\J lT^Dn HN j hH / U 9 0 \===\ II / / N \y^°' oz^y'^occoc5 N^\J / T^Dn u HJN / hH J / N^\J-VDU 9 0? O-o1T J YLNHYV ° O'^ fl / LJ / N^XCF3HNX-NJU^sy5Attorney Ref: 41827-65010 (044WO)HN j NA hH J' '' / V P0 \==\II / / N AA^o / A~ vA YHw ’ oA / A XDHNLXN JAA0Z D5 HN— AA^ANVJ° N'NH °^XZ / A o= J\ \ / / \\ — / / NVH / N7y AVVTV AX5 Hr / v<oIN Q N'NH °^\<f / Y oA ( k A \HN / ykA rvA0'0D 5Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO)Attorney Ref: 41827-65010 (044WO) or a pharmaceutically acceptable salt of any of the above.

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 38 and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.

40. A method of treating a Ras protein-related disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39.

41. A method of inhibiting a Ras protein or variant thereof in a subject comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39.

42. A method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39.

43. The method of claim 42, wherein the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer, esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma, thyroid cancer, cardiac cancer, biliary tract cancer, and hematological cancer.

44. The method of claim 42, wherein the cancer is selected from carcinoma, sarcoma, melanoma, lymphoma, and leukemia.

45. The method of claim 42, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

46. The method of any one of claims 42 to 45, wherein the cancer is a primary cancer or a metastatic cancer.

47. Use of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, in the manufacture of a medicament for the treatment of a disease or disorder.

48. The use of claim 47, wherein the disease is cancer.

49. The use of claim 48, wherein the cancer is selected from breast cancer, prostate cancer, bone cancer, brain cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, liposarcoma, liver cancer, rhabdoid cancer, sarcoma, skin cancer, kidney cancer, stomach cancer, pancreatic cancer,Attorney Ref: 41827-65010 (044WO) esophageal cancer, head and neck cancer, bladder cancer, leukemia, lymphoma, thyroid cancer, cardiac cancer, biliary tract cancer, and hematological cancer.

50. The use of claim 48, wherein the cancer is selected from carcinoma, sarcoma, melanoma, lymphoma, and leukemia.

51. The use of claim 48, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

52. The use of any one of claims 48 to 51, wherein the cancer is a primary cancer or a metastatic cancer.

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