Ribonucleotide reductase (RNR) compositions and methods of use

Abstract

Provided herein are methods of treatment comprising administering a selective ribonucleotide reductase (RNR) inhibitor in combination with other therapeutic agents, thereby treating cancer and preventing or reversing resistance to the therapeutic agents.

Description

RIBONUCLEOTIDE REDUCTASE (RNR) COMPOSITIONS AND METHODS OF USECROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 580,096 filed September 1, 2023 and U. S. Provisional Application Serial No. 63 / 589,547 filed October 11, 2023; which are hereby incorporated by reference in their entirety.BACKGROUND

[0002] Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides by removing the 2’-hydroxyl group of the ribose ring of nucleotide diphosphates. These deoxyribonucleotides are used in the synthesis of DNA.SUMMARY

[0003] In an aspect, provided herein are methods of delaying or preventing resistance to a therapeutic agent in a subject in need thereof comprising administering a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject, wherein the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and / or a receptor tyrosine kinase (RTK) inhibitor, and wherein the method results in a delay or prevention of resistance by a tumor or tumor cells to the therapeutic agent. In some embodiments, the method results in the inhibition of growth of the tumor or proliferation of the tumor cells. In some embodiments, the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an S0S1 inhibitor. In some embodiments, the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic. In some embodiments, the therapeutic agent and the RNR inhibitor are administered concurrently. The method of any one of claims 1 to 13, wherein the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumorcells. In some embodiments, the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, KRASG12Vor a KRASG12Dmutation. In some embodiments, the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer. In some embodiments, the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC- 376, garsorasib, GEC-255, GF-105, GH-35, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof. In some embodiments, the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600E mutation. In some embodiments, the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer. In some embodiments, the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof. In some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS 1553. In some embodiments, the method further comprises administering an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH- 7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD- 9008, E01001, E-10C, epertinib, epitinib (HMPL-813), erlotinib, ES-072, FCN-411, FHND-9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX-07,HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN-023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694- A, NT-004, OBX1-012, olafertinib, olmutinib, ORIC-114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL-1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ- 13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof. In some embodiments, prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene. In some embodiments, the mutation is BRAFV600E, KRASG12C, KRASG12Vor KRASG12D. In some embodiments, the mutation is selected from a KRAS mutation described in Table 1. In some embodiments, the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof. In some embodiments, the amplification of the RTK or MAPK gene is detected by NGS. In some embodiments, the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.

[0004] In another aspect, provided herein are methods of treating cancer in a subject in need thereof comprising administering a selective ribonucleotide reductase (RNR) inhibitor and a therapeutic agent to the subject, wherein the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and / or a receptor tyrosine kinase (RTK) inhibitor. In some embodiments, the method results in the inhibition of growth of the tumor or proliferation of the tumor cells. In some embodiments, the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an S0S1 inhibitor. In some embodiments, inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone. In some embodiments, the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic. In some embodiments, the therapeutic agent and the RNR inhibitor are administered concurrently. The method of any one of claims 1 to 13, wherein the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and thetherapeutic agent. In some embodiments, the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells. In some embodiments, the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, a KRASG12V, or a KRASG12Dmutation. In some embodiments, the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer. In some embodiments, the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, HBI-2438, HRS- 4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL- 15293, ZG-19018, and any combination thereof. In some embodiments, the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600E mutation. In some embodiments, the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer. In some embodiments, the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL- 102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof. In some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS1553. In some embodiments, the method further comprises administering an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL- 1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS- 2087, DZD-9008, E01001, E-10C, epertinib, epitinib (HMPL-813), erlotinib, ES-072, FCN-411, FHND-9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX- 07, HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN- 023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694- A, NT-004, OBX1-012, olafertinib, olmutinib, ORIC-114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL-1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ- 13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof. In some embodiments, prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene. In some embodiments, the mutation is BRAFV600E, KRASG12C, KRASG12V, or KRASG12D. In some embodiments, the mutation is selected from a KRAS mutation described in Table 1. In some embodiments, the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof. In some embodiments, the amplification of the RTK or MAPK gene is detected by NGS. In some embodiments, the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.

[0005] In a further aspect, provided herein are methods of treating a subject having a tumor or tumor cells resistant to a therapeutic agent comprising administering a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject, wherein the therapeutic agent is a mitogen -activated protein kinase (MAPK) pathway inhibitor and / or a receptor tyrosine kinase (RTK) inhibitor, wherein the subject has been previously treated with the therapeutic agent and demonstrated decreased responsiveness or resistance to the therapeutic agent, and wherein the method results in inhibition of growth of the tumor or proliferation of the tumor cells. In some embodiments, the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an SOS 1 inhibitor. In some embodiments, inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone. In some embodiments, the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic. In some embodiments, the therapeutic agent and the RNR inhibitor are administered concurrently. The method of any one of claims 1 to 13, wherein the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises awashout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells. In some embodiments, the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, a KRASG12V, or a KRASG12Dmutation. In some embodiments, the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer. In some embodiments, the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS- 4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY- 3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof. In some embodiments, the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600E mutation. In some embodiments, the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer. In some embodiments, the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof. In some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS 1553. In some embodiments, the method further comprises administering an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinibmesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD- 9008, E01001, E-10C, epertinib, epitinib (HMPL-813), erlotinib, ES-072, FCN-411, FHND-9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX-07, HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN-023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694- A, NT-004, OBX1-012, olafertinib, olmutinib, ORIC-114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL-1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ- 13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof. In some embodiments, prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene. In some embodiments, the mutation is BRAFV600E, KRASG12C, KRASG12V, or KRASG12D. In some embodiments, the mutation is selected from a KRAS mutation described in Table 1. In some embodiments, the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof. In some embodiments, the amplification of the RTK or MAPK gene is detected by NGS. In some embodiments, the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.

[0006] In another aspect, provided herein are methods of treating a tumor or tumor cells in a subject that are resistant to a therapeutic agent, comprising administering a selective ribonucleotide reductase (RNR) inhibitor to the subject, wherein the tumor or tumor cells comprise a focal amplification of a mitogen activated protein kinase (MAPK) pathway gene or a receptor tyrosine kinase (RTK) gene, wherein the therapeutic agent targets the MAPK pathway gene or the RTK gene, and where the method results in inhibition of growth of the tumor or proliferation of the tumor cells. In some embodiments, the therapeutic agent targets KRAS. In some embodiments, the therapeutic agent targets KRASG12C, KRASG12V, or KRASG12D. In some embodiments, the therapeutic agent targets a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the therapeutic agent is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is selected from the group consisting of adagrasib, AIG Oncol, BBO- 8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI-2438, HRS-4642, HS- 10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof. In some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS 1553. Insome embodiments, the copy number of one or more oncogenes associated with the focal amplification is reduced after administering the selective RNR inhibitor.

[0007] A method of treating a tumor or tumor cells comprising administering a selective ribonucleotide reductase (RNR) inhibitor, wherein the tumor cells comprise ecDNA-derived amplification of an oncogene, and wherein the treatment reduced the level of amplification of the oncogene. In some embodiments, the size of the tumor or growth of the tumor or growth of the tumor cells is inhibited after treatment with the selective RNR inhibitor. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS1553.INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] An understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0010] FIG. 1 shows mean tumor growth of CT26WT E3 G12C KRAS mutant tumor cells implanted in mice treated with vehicle compared with mice treated with adagrasib.

[0011] FIG. 2 shows Kras positive ecDNA manually quantified in ex vivo metaphase arrested tumors cells isolated from CT26WT E3 G12C KRAS tumors grown in mice that are untreated or treated with vehicle compared with mice treated with adagrasib.

[0012] FIG. 3 shows mean tumor growth of CT26WT E3 G12C KRAS mutant tumor cells implanted in mice after starting treatment with vehicle, adagrasib, Compound 1, or Compound 1 with adagrasib.

[0013] FIG. 4 shows mean tumor growth of CT26WT E3 G12C KRAS mutant adagrasib resistant ecDNA+ tumor cells implanted in mice after starting treatment with vehicle, adagrasib, Compound 1, or Compound 1 with adagrasib.

[0014] FIG. 5 shows mean tumor growth of WiDr V600E BRAF mutant tumor cells implanted in mice after starting treatment with vehicle, cetuximab and encorafenib, Compound 1, or Compound 1 with cetuximab and encorafenib.

[0015] FIG. 6A shows percent of tumors that are less than 500 mm3for tumors established in mice implanted with WiDr V600E BRAF mutant tumor cells during the course of treatment with vehicle, cetuximab and encorafenib, Compound 1, or Compound 1 with cetuximab and encorafenib.

[0016] FIG. 6B shows mean body weight change from starting mean body weight in mice treated with vehicle, cetuximab and encorafenib, Compound 1, or Compound 1 with cetuximab and encorafenib.

[0017] FIG. 7 shows mean tumor growth of SNU-16 FGFR2 ecDNA+ tumor cells implanted in mice after treatment with vehicle only; infigratinib, Compound 1 or Compound 1 and infigratinib.

[0018] FIGS. 8A-E show the impact on ecDNA levels upon inhibition of RNR by Compound 1 treatment using multiple orthogonal readouts. FIG. 8A shows cell-death and viability assessment using Trypan Blue staining. FIG. 8B shows FISH based cytogenetic analysis of cells treated with Compound 1. FIG. 8C and 8D show quantification of the FISH signals, using the image quantification platform called ImageJ (Tool, Find maxima). FIG. 8E shows the reduction in ecDNA cargo oncoprotein expression of MYC and FGFR2 and replication stress (RS), DNA damage and cell death protein biomarkers using western blotting.

[0019] FIGS. 9 A-C show that Compound 1 prevents ecDNA -mediated resistance associated with KRASG12C inhibitor in a colorectal cancer model of CT26 cells engineered to express the Kras G12C allele (CT26WT E3), using this cell line in its non-amplified state and after the cells developed resistance to adagrasib. FIG. 9A shows ecDNA and Kras amplification via FISH for CT26 KRASG12C mutant nonamplified cells and adagrasib resistant tumor cells with KRASG12C amplified on ecDNA. FIG. 9B shows a cell proliferation assay confirming resistance generation against adagrasib. FIG. 9C shows activation of the KRAS and the flux through the KRAS pathway using western blotting,

[0020] FIG. 10A shows the antitumor efficacy of Compound 1 (triangle) and adagrasib (square) monotherapy and Compound 1 plus adagrasib combination therapy (diamond) in the CT26WT E3 tumor model as measured by tumor volume. Data shown as mean ± SEM (standard error of the mean) for each treatment arm. The combination therapy of Compound 1 at 50mg / kg SC BID Q2D plus adagrasib also showed significantly greater antitumor activity when compared with adagrasib monotherapy (**P <0.01) on Study Day 30. Significance between adagrasib monotherapy and Compound 1 plus adagrasib combination therapy arms were determined by unpaired t test using GraphPad Prism software. **P valueO.Ol. BID Q2D: twice per day, every other day, PO: orally, QD: once per day, SC: subcutaneous.

[0021] FIG. 10B shows percent of tumors that are less than 500 mm3for tumors established in mice implanted with CT26WT E3 cells during the course of treatment of Compound 1 and adagrasib monotherapy as compared to Compound 1 plus adagrasib combination therapy.

[0022] FIG. 10C shows the Kras gene copy number determined in terminal tumors and shows that adagrasib results in Kras amplification in resistant tumors and Compound 1 abrogates this amplification.

[0023] FIG. HA shows the schema for the dosing of the KRAS inhibitor MRTX1133 and Compound 1 over the 8 weeks in Ct26 / 't''’(,l 2l)colorectal cells.

[0024] FIG. 11B shows a FISH image of a parental (untreated) CT26 / ;''t''"(,l 2l)CRC colorectal cells and the appearance of ecDNA in the cells treated with increasing doses of MRTX1133 which developed acquired resistance to KRASG12Di by driving KRAS amplifications on ecDNA.

[0025] FIG. 11C shows cell viability of CT26Xra?'G12DCRC colorectal cells parental line, cells that developed resistance to MRTX1133 and cells treated with a combination treatment ofMRTX1 133 + Compound 1, showing that the combination led to a significant antiproliferation activity when compared to MRTX1133 alone treated cells (left graph). The bar graph (right graph) shows the copy number (CNV) of KRAS at week 8 for the cells treated in the graph on the left. The combination treatment shows suppression of resistance mediated KRAS amplifications is concomitant with the reduction of cell viability shown in graph on left.DETAILED DESCRIPTION

[0026] Ribonucleotide reductase (RNR) plays a fundamental role in supporting extrachromosomal DNA (ecDNA) assembly and repair. As such, cellular reliance on RNR is elevated in ecDNA containing cells. RNR is the rate-limiting enzyme responsible for cellular production of deoxyribonucleotide triphosphate (dNTP), the building blocks for DNA, including assembly and repair of ecDNA. It has been found that therapeutic inhibition of RNR dysregulates dNTP production and creates synthetic lethality in ecDNA+ tumor cells. RNR is clinically validated via gemcitabine (gem) and hydroxyurea (HU). However, non- selective RNR inhibitors such as gem and HU have suboptimal potency (HU) or lack of oral bioavailability (gem), which limits their efficacy and safety in treating ecDNA+ cancers. In contrast, selective RNR inhibition results in depletion of dNTPs and reduced ecDNA levels in ecDNA-enabled tumor cells, which leads to tumor cell death.Methods of Treatment

[0027] In an aspect, provided herein are methods of treating cancer in a subject comprising administration of a selective ribonucleotide reductase (RNR) inhibitor. In some embodiments, the cancer is resistant to a therapeutic agent. In some embodiments, the method comprises administering a therapeutic agent with the RNR inhibitor. In some embodiments, the method treats resistance to the therapeutic agent. In some embodiments, the method prevents or delays resistance to the therapeutic agent.Methods of Delaying or Preventing Resistance

[0028] In an aspect, provided herein are methods of delaying or preventing resistance to a therapeutic agent in a subject. In some embodiments, the method comprises administering a selective RNR inhibitor and the therapeutic agent to the subject. In some embodiments, the therapeutic agent is a mitogen- activated protein kinase (MAPK) pathway inhibitor. In some embodiments, the therapeutic agent is a receptor tyrosine kinase (RTK) inhibitor. In some embodiments, the method results in a delay or prevention of resistance by a tumor or tumor cells to the therapeutic agent. In some embodiments, the method results in the inhibition of growth of the tumor or proliferation of the tumor cells.

[0029] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.

[0030] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor or an S0S1 inhibitor.

[0031] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone. In some embodiments, the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.

[0032] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent and the RNR inhibitor are administered concurrently. In some embodiments, the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.

[0033] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.

[0034] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent.

[0035] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, a KRASG12Vor a KRASG12Dmutation. In some embodiments, the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer,glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.

[0036] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH- 35, glecirosib, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC- 6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.

[0037] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600Emutation. In some embodiments, the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.

[0038] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.

[0039] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the RNR inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0040] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the RNR inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0041] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the method further comprises administering an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH- 7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD- 9008, E01001, E-10C, epertinib, epitinib (HMPL-813), erlotinib, ES-072, FCN-411, FHND-9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX-07, HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN-023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694- A, NT-004, OBX1-012, olafertinib, olmutinib, ORIC-114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL-1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ- 13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof.

[0042] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene. In some embodiments, the mutation is BRAFV600E, KRASG12C, KRASG12Vor KRASG12D. In some embodiments, the mutation is selected from a KRAS mutation described in Table 1. In some embodiments, the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof. In some embodiments, the amplification of the RTK or MAPK gene is detected by NGS.

[0043] In various aspects of methods of delaying or preventing resistance to a therapeutic agent provided herein, in some embodiments, the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.Methods of Treating Cancer

[0044] In an aspect, provided herein are methods of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering a selective ribonucleotide reductase (RNR) inhibitor and a therapeutic agent to the subject. In some embodiments, the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor. In some embodiments, the therapeutic agent is a receptor tyrosine kinase (RTK) inhibitor. In some embodiments, the method results in inhibition of growth of the tumor or proliferation of the tumor cells.

[0045] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.

[0046] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor or an S0S1 inhibitor.

[0047] In various aspects of methods of treating cancer provided herein, in some embodiments, inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone. In some embodiments, the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.

[0048] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent and the RNR inhibitor are administered concurrently. In some embodiments, the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.

[0049] In various aspects of methods of treating cancer provided herein, in some embodiments, the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.

[0050] In various aspects of methods of treating cancer provided herein, in some embodiments, the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent.

[0051] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, a KRASG12Vor a KRASG12Dmutation. In some embodiments, the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.

[0052] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-I8239II, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-I05, GH-35, glecirosib, HBI-2438, HRS- 4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-629I, RMC-9805, sotorasib, YL- 15293, ZG-19018, and any combination thereof.

[0053] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600Emutation. In some embodiments, the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.

[0054] In various aspects of methods of treating cancer provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL- 102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.

[0055] In various aspects of methods of treating cancer provided herein, in some embodiments, the RNR inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0056] In various aspects of methods of treating cancer provided herein, in some embodiments, the RNR inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0057] In various aspects of methods of treating cancer provided herein, in some embodiments, the method further comprises administering an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI- 361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD-9008, E01001, E-10C, epertinib, epitinib (HMPL- 813), erlotinib, ES-072, FCN-411, FHND-9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX-07, HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN-023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694-A, NT-004, OBX1-012, olafertinib, olmutinib, ORIC- 114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL-1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ-13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof.

[0058] In various aspects of methods of treating cancer provided herein, in some embodiments, prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene. In some embodiments, the mutation is BRAFV600E, KRASG12C, KRASG12Vor KRASG12D. In some embodiments, the mutation is selected from a KRAS mutation described in Table 1. In some embodiments, the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof. In some embodiments, the amplification of the RTK or MAPK gene is detected by NGS.

[0059] In various aspects of methods of treating cancer provided herein, in some embodiments, the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.Methods of Treating a Tumor Resistant to a Therapeutic Agent

[0060] In an aspect, provided herein, are methods of treating a subject having a tumor or tumor cells resistant to a therapeutic agent. In some embodiments, the method comprises administering a ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject. In some embodiments, the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor. In some embodiments, the therapeutic agent is a receptor tyrosine kinase (RTK) inhibitor. In some embodiments, the subject has been previously treated with the therapeutic agent. In some embodiments, after treatment the subject demonstrated decreased responsiveness to the therapeutic agent. In some embodiments, after treatment the subject demonstrated resistance to the therapeutic agent. In some embodiments, the method results in inhibition of growth of the tumor or proliferation of the tumor cells.

[0061] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.

[0062] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor or an S0S1 inhibitor.

[0063] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone. In some embodiments, the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.

[0064] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent and the RNR inhibitor are administered concurrently. In some embodiments, the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.

[0065] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent. In some embodiments, the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.

[0066] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent.

[0067] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, a KRASG12Vor a KRASG12Dmutation. In some embodiments, the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1. In some embodiments, the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.

[0068] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI- 2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.

[0069] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600Emutation. In some embodiments, the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.

[0070] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.

[0071] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0072] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0073] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, the method further comprises administering an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, B LU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB- 017, DFP- 17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD-9008, E01001, E-10C, epertinib, epitinib (HMPL-813), erlotinib, ES-072, FCN-411, FHND-9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX-07, HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN-023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694-A, NT-004, OBX1-012, olafertinib,olmutinib, ORIC-114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL- 1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ-13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof.

[0074] In various aspects of methods of treating a resistant tumor or tumor cells provided herein, in some embodiments, prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene. In some embodiments, the mutation is BRAFV600E, or KRASG12C, KRASG12Vor KRASG12D. In some embodiments, the mutation is selected from a KRAS mutation described in Table 1. In some embodiments, the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof. In some embodiments, the amplification of the RTK or MAPK gene is detected by NGS.

[0075] In another aspect, provided herein are methods of treating a tumor or tumor cells that are resistant to a therapeutic agent. In some embodiments, the method comprises administering a selective ribonucleotide reductase (RNR) inhibitor to the subject, wherein the tumor or tumor cells comprise a focal amplification of a mitogen activated protein kinase (MAPK) pathway gene or a receptor tyrosine kinase (RTK) gene, wherein the therapeutic agent targets the MAPK pathway gene or the RTK gene, and where the method results in inhibition of growth of the tumor or proliferation of the tumor cells.

[0076] In various aspects of treating a tumor or tumor cells that are resistant to a therapeutic agent provided herein, in some embodiments, the therapeutic agent targets KRAS. In some embodiments, the therapeutic agent targets KRASG12C, KRASG12Vor KRASG12D. In some embodiments, the therapeutic agent targets a KRAS mutation selected from a KRAS mutation described in Table 1.

[0077] In various aspects of treating a tumor or tumor cells that are resistant to a therapeutic agent provided herein, in some embodiments, the focal amplification is comprised on ecDNA.

[0078] In various aspects of treating a tumor or tumor cells that are resistant to a therapeutic agent provided herein, in some embodiments, the therapeutic agent is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC- 376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY- 3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.

[0079] In various aspects of treating a tumor or tumor cells that are resistant to a therapeutic agent provided herein, in some embodiments, the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0080] In various aspects of treating a tumor or tumor cells that are resistant to a therapeutic agent provided herein, in some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0081] In various aspects of treating a tumor or tumor cells that are resistant to a therapeutic agent provided herein, in some embodiments, the copy number of one or more oncogenes associated with the focal amplification is reduced after administering the selective RNR inhibitor.Selective RNR Inhibitors

[0082] In an aspect, selective RNR inhibitors provided herein have an optimized profile including potency; selectivity for RNR; oral bioavailability; favorable absorption, distribution, metabolism, and excretion (ADME); and clean safety pharmacology.

[0083] In some embodiments, the selective RNR inhibitor is TAS 1553.

[0084] In some embodiments, the selective RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (I), wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4;R1, R2, R3, and R4are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Ring C is a 4- to 8-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl; or 2 R5on the same carbon are taken together to form an oxo; p is 0-4;Ring A is a 5 -membered ring comprising 1-4 heteroatoms selected from the group consisting of O, S, and N;each R6is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R6on the same atom are taken together to form an oxo; n is 0-3; R7is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R8is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R9is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R9a; or two R9on the same atom are taken together to form an oxo; each R9ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R9aon the same atom are taken together to form an oxo; m is 0-5; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents that is oxo, halogen, - CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, - NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents that is oxo, halogen, - CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, - NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents that is oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more substituents that is oxo, halogen, -CN, -OH, -OCH3, - S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0085] In some embodiments of a compound of Formula (I), the compound is of Formula:.

[0086] In some embodiments, the selective RNR inhibitor is a compound of Formula (I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (1-1).

[0087] In some embodiments of a compound of Formula (1-1), the compound is of Formula:

[0088] In some embodiments, the selective RNR inhibitor is a compound of Formula (1-2), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (1-2).

[0089] In some embodiments of a compound of Formula (1-2), the compound is of Formula:

[0090] In some embodiments, the selective RNR inhibitor is a compound of Formula (1-3), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (1-3).

[0091] In some embodiments of a compound of Formula (1-3), the compound is of Formula:

[0092] In some embodiments, the selective RNR inhibitor is a compound of Formula (1-4), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (1-4).

[0093] In some embodiments of a compound of Formula (1-4), the compound is of Formula:

[0094] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered ring comprising 1 or 2 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered ring comprising 2 or 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 2-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 3 or 4 heteroatoms selected from the group consisting of O, S, and N.

[0095] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5-membered ring comprising 1 heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 2 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I- 4), Ring A is a 5 -membered ring comprising 3 heteroatoms selected from the group consisting of O, S, andN. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 4 heteroatoms selected from the group consisting of O, S, and N.

[0096] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered ring comprising 1 or 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 2 or 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 2-4 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 3 or 4 heteroatoms selected from the group consisting of O and N.

[0097] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5-membered ring comprising 1 heteroatom selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 2 heteroatoms selected from the group consisting of O and N.

[0098] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5-membered ring comprising 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 4 heteroatoms selected from the group consisting of O and N.

[0099] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered heterocycloalkyl or a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered heterocycloalkyl comprising one to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5 -membered heterocycloalkyl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5 -membered heterocycloalkyl comprising three to four heteroatoms selected from the group consisting ofO, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered heteroaryl comprising one to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered heteroaryl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered heteroaryl comprising three to four heteroatoms selected from the group consisting of O, S, and N.

[0100] In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a triazole or tetrazole. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a triazole. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a tetrazole. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 2,3-dihydro-l,3,4-oxadiazole.

[0101] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), each R6is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R6on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), each R6is independently deuterium, halogen, or C1-C6alkyl; or two R6on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), each R6is independently C1-C6alkyl; or two R6on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), each R6is independently C1-C6alkyl.

[0102] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), two R6on the same atom are taken together to form an oxo.

[0103] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0-2. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0 or 1. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 1 or 2. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 2 or 3. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 1. In some embodiments of a compound of Formula (I) or (I- 1)-(I-4), n is 2. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 3.

[0104] In some embodiments of a compound of Formula (I), the compound is of Formula (Ia):wherein R6’is hydrogen or C1-C6alkyl.

[0105] In some embodiments of a compound of Formula (Ia), the compound is of Formula:.

[0106] In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X1is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X1is CR1.

[0107] In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X2is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X2is CR2.

[0108] In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X3is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X3is CR3.

[0109] In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), X4is N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), X4is CR4.

[0110] In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 5- to 7- membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6- to 7-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I- 4), Ring C is a 5- to 6-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 6-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.

[0111] In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5- to 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6- to 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5- to 6- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 5- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 8- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.

[0112] In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 5- to 7- membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6- to 7-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 7-membered heterocycloalkyl.

[0113] In some embodiments of a compound of Formula (I) or (la), the compound is of Formula (lb):wherein R6’is hydrogen or C1-C6alkyl; and each R5’is independently hydrogen or R5.

[0114] In some embodiments of a compound of Formula (Ib), the compound is of Formula:.

[0115] In some embodiments of a compound of Formula (Ib), each R5’is independently hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; or 2 R5on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (Ib), each R5’is independently hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (Ib), each R5’is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (Ib), each R5’is hydrogen. In some embodiments of a compound of Formula (Ib), each R5’is independently hydrogen or deuterium.

[0116] In some embodiments of a compound of Formula (I) or (Ia), the compound is of Formula (Ic):Formula (Ic); wherein R6’is hydrogen or C1-C6alkyl.

[0117] In some embodiments of a compound of Formula (Ic), the compound is of Formula:.

[0118] In some embodiments of a compound of Formula (I) or (Ia), the compound is of Formula (Id):Formula (Id); wherein R6’is hydrogen or C1-C6alkyl.

[0119] In some embodiments of a compound of Formula (Id), the compound is of Formula:.

[0120] In some embodiments of a compound of Formula (Ia)-(Id), R6’is hydrogen.

[0121] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R5is independently deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; or 2 R5on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (I), (Ia)- (Id), or (I-1)-(I-4), each R5is independently deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R5is independently deuterium. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R5is independently C1-C6alkyl.

[0122] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 0 or 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 0. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)- (I-4), p is 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 3.

[0123] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1, R2, R3, and R4are independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1, R2, R3, and R4are independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1, R2, R3, and R4are independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1, R2, R3, and R4are independently hydrogen, or halogen, -ORa.

[0124] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R1is halogen.

[0125] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R2is halogen.

[0126] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In someembodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R3is halogen.

[0127] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is hydrogen, deuterium, halogen, - CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R4is halogen.

[0128] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is deuterium, halogen, -CN, -NO2, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is C1-C6alkyl or cycloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R7is C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)- (Id), or (I-1)-(I-4), R7is methyl.

[0129] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R8is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R8is hydrogen.

[0130] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is phenyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is 6-membered heteroaryl.

[0131] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R9is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R9a; or two R9on the same atom are taken together to form an oxo.

[0132] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R9is independently deuterium, halogen, -CN, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R9a.

[0133] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R9is independently halogen or C1-C6alkyl.

[0134] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R9ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more of deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0135] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R9ais independently deuterium, halogen, -ORa, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more of deuterium, halogen, - CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0136] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0 or 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0-2. In some embodiments of a compound of Formula (I), (Ia)- (Id), or (I-1)-(I-4), m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 4.

[0137] In some embodiments, the selective RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (II), wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4;R1is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;R2is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;R3is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;R4is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl,C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; Ring C is a 5- to 8-membered heterocycloalkyl comprising one or two additional heteroatoms selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, and -NR10-; R10is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R10a; each R10ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R5is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R5on the same carbon are taken together to form an oxo; or two R5on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R5on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; or one R5and R10are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; p is 0-4; Ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; each R6is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R6on the same atom are taken together to form an oxo; n is 0-3;R7is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R8is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R9is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R9a; or two R9on the same atom are taken together to form an oxo; each R9ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R9aon the same atom are taken together to form an oxo; m is 0-5; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, - C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1- C3heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom are taken together to form an oxo.

[0138] In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound is of Formula:.

[0139] In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one or two additional heteroatoms selected from the group consisting of -O-, -S-, and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one or two additional heteroatoms selected from the group consisting of - S(=O)- and -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one or two additional heteroatoms selected from the group consisting of -O- and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and - NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom that is -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom that is -S-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom thatis -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)-.

[0140] In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and - NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -S-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)-.

[0141] In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and - NR10-. -. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -S-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)-.

[0142] In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom that is - NR10-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkylcomprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (II), Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom that is -S-.

[0143] In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and -NR10-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is - NR10-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -S-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -S-.

[0144] In some embodiments of a compound of Formula (II), each R5is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R5is independently deuterium, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (II), each R5is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R5is independently C1-C6alkyl.

[0145] In some embodiments of a compound of Formula (II), two R5on the same carbon are taken together to form an oxo.

[0146] In some embodiments of a compound of Formula (II), two R5on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.

[0147] In some embodiments of a compound of Formula (II), two R5on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0148] In some embodiments of a compound of Formula (II), one R5and R10are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0149] In some embodiments of a compound of Formula (II), p is 0-3. In some embodiments of a compound of Formula (II), p is 0-2. In some embodiments of a compound of Formula (II), p is 0 or 1. Insome embodiments of a compound of Formula (II), p is 1 or 2. In some embodiments of a compound of Formula (II), p is 1-3. In some embodiments of a compound of Formula (II), p is 1. In some embodiments of a compound of Formula (II), p is 2. In some embodiments of a compound of Formula (II), p is 3.

[0150] In some embodiments, the compound of Formula (II) is of Formula (Ila):wherein:X is -O-, -S-, -S(=O)-, -S(=O)2-, or -NR10-; each R5is independently hydrogen or R5; or two R5on the same carbon are taken together to form an oxo; or two R5on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or one R5and R10are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0151] In some embodiments of a compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound is of Formula:

[0152] In some embodiments, the compound of Formula (II) is of Formula (lib):wherein:X is -O-, -S-, -S(=O)-, -S(=O)2-, or -NR10-;each R5is independently hydrogen or R5; or two R5on the same carbon are taken together to form an oxo; or two R5on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R5on adjacent carbons are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; or one R5and R10are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0153] In some embodiments of a compound of Formula (lib), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound is of Formula:

[0154] In some embodiments, the compound of Formula (II) is of Formula (lie):wherein:X is -O-, -S-, -S(=O)-, -S(=O)2-, or -NR10-; each R5is independently hydrogen or R5; or two R5on the same carbon are taken together to form an oxo; or two R5on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or one R5and R10are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0155] In some embodiments of a compound of Formula (lie), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound is of Formula:.

[0156] In some embodiments of a compound of Formula (IIa)-(IIc), X is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of a compound of Formula (IIa)-(IIc), X is -O-, -S-, or -NR10-. In some embodiments of a compound of Formula (IIa)-(IIc), X is -O- or -NR10-. In some embodiments of a compound of Formula (IIa)-(IIc), X is -O-. In some embodiments of a compound of Formula (IIa)-(IIc), X is -NR10-.

[0157] In some embodiments of a compound of Formula (IIa)-(IIc), each R5’is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IIa)-(IIc), each R5’is independently hydrogen, deuterium, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IIa)-(IIc), each R5’is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R5is independently hydrogen or C1-C6alkyl.

[0158] In some embodiments of a compound of Formula (IIa)-(IIc), two R5’on the same carbon are taken together to form an oxo.

[0159] In some embodiments of a compound of Formula (IIa)-(IIc), two R5’on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.

[0160] In some embodiments of a compound of Formula (IIa)-(IIc), one R5’and R10are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

[0161] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R10is hydrogen, -S(=O)2Ra, - C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R10a. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R10is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl is optionally and independently substituted with one or more R10a. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R10is C1-C6alkyl.

[0162] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R10ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R10ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R10ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R10ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.

[0163] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5- membered heterocycloalkyl comprising one to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heterocycloalkyl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heterocycloalkyl comprising three to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heteroaryl comprising one to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heteroaryl comprising two to four heteroatoms selected from the group consisting of O, S, and N.

[0164] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 5-membered heteroaryl comprising three to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a triazole or tetrazole. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a triazole. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a tetrazole. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring A is a 2,3-dihydro-1,3,4-oxadiazole.

[0165] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R6is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R6on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R6is independently deuterium, halogen, or C1-C6alkyl; or two R6on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R6on the same atom are taken together to form an oxo.

[0166] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 0-3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 0-2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa)- (IIc), n is 2 or 3.

[0167] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 3.

[0168] In some embodiments of a compound of Formula (II) or (IIa)-(IIc),wherein R6’is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula

[0169] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X1is CR1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X1is N.

[0170] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen, deuterium, halogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl; wherein the alkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen, deuterium, halogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen, -C(=O)Ra, C1-C6alkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R1is hydrogen.

[0171] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X2is CR2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X2is N.

[0172] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or(IIa)-(IIc), R2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R2is hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R2is halogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R2is chloro.

[0173] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X3is CR3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X3is N.

[0174] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R3is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R3is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, - C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R3is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R3is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl, C1-C6heteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R3is hydrogen.

[0175] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X4is CR4. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X4is N.

[0176] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen, deuterium, halogen, -CN, OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen, deuterium, halogen, -CN, OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen, deuterium, halogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, orC1-C6heteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, orC1-C6heteroalkyl. In some embodiments of acompound of Formula (II) or (IIa)-(IIc), R4is hydrogen, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen or -C(=O)Ra. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is hydrogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R4is -C(=O)Ra.

[0177] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R7is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R7is C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R7is C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R7is C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R7is halogen, -CN, -NO2, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R7is C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl.

[0178] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R8is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R8is hydrogen.

[0179] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is phenyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is pyridinyl.

[0180] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R9is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R9is independently halogen or C1-C6alkyl.

[0181] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 0-2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1-3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 2 or 3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 0. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 3.

[0182] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents that is oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl,C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl.

[0183] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents that is oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rais hydrogen.

[0184] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents that is oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen.

[0185] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more substituents that is oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, - S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl,C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more substituents that is oxo, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl.

[0186] In some embodiments, the selective RNR inhibitor is a compound, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is selected from a compound of Table 2: TABLE 2

[0187] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.

[0188] In some embodiments, the selective RNR inhibitor is a compound, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is selected from a compound of Table 3: TABLE 3WSGR Docket No.57547-734.601WSGR Docket No.57547-734.601WSGR Docket No.57547-734.601WSGR Docket No.57547-734.601WSGR Docket No.57547-734.601

[0189] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer. Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[0190] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. The compounds described herein include all rotamers and “atropisomers as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniquesbased upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[0191] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention.Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritium, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability.Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by deuteroalkyl substituents.

[0192] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0193] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0194] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, orby separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0195] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0196] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1 -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0197] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-C4 alkyl)4 hydroxide, and the like.

[0198] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0199] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0200] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Certain Definitions

[0201] As used herein the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which can depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. As another example, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. With respect to biological systems or processes, the term “about” can mean within an order of magnitude, such as within 5-fold or within 2-fold of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” means within an acceptable error range for the particular value.

[0202] The term “subject,” as used herein, generally refers to a vertebrate, such as a mammal (e.g., a human). Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets (e.g., a dog or a cat). Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed. In some embodiments, the subject is a patient, e.g., a human patient. In some embodiments, the subject is symptomatic with respect to a disease (e.g., cancer). Alternatively, in some cases, the subject is asymptomatic with respect to the disease. In some cases, the subject does not have the disease.

[0203] The term “biological sample,” as used herein, generally refers to a sample derived from or obtained from a subject, such as a mammal (e.g., a human). Biological samples are contemplated toinclude but are not limited to, hair, fingernails, skin, sweat, tears, ocular fluids, nasal swab or nasopharyngeal wash, sputum, throat swab, saliva, mucus, blood, serum, plasma, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, earwax, oil, glandular secretions, bile, lymph, pus, microbiota, meconium, breast milk, bone marrow, bone, CNS tissue, cerebrospinal fluid, adipose tissue, synovial fluid, stool, gastric fluid, urine, semen, vaginal secretions, stomach, small intestine, large intestine, rectum, pancreas, liver, kidney, bladder, lung, and other tissues and fluids derived from or obtained from a subject. In some cases, the subject is diagnosed with the disease and / or has a biomarker for the disease.

[0204] The term “treating” as used herein, generally refers to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect. In some cases, the effect is prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or is therapeutic in terms of effecting a partial or complete cure for a disease and / or one or more symptoms of the disease. "Treatment," as used herein, may include treatment of a tumor in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. Treating may refer to any indicia of success in the treatment or amelioration or prevention of a cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician. Accordingly, the term "treating" includes the administration of the compounds or agents of the present invention to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with cancer or other diseases. The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject.

[0205] The term “tumor” or “tumor cells” as used herein, generally refers to cells that grow and divide more than they should or do not die when they should. In some cases, tumor cells are present in a solid mass, such as a solid tumor, or in some cases, tumor cells are found in a non-solid form, such as in blood cancers. Tumor or tumor cells also can include metastasis or metastasizing cells, where cancer cells break away from the original (primary) tumor and may form a new tumor in other organs or tissues of the body.

[0206] The term “oncogene” as used herein, generally refers to a gene that has the potential to cause cancer when inappropriately activated. In tumors or tumor cells, these genes are often mutated to remove negative regulatory domains or expressed at high levels.

[0207] The term “ecDNA signature” as used herein, generally refers to one or more characteristics common to tumors or tumor cells that are ecDNA+. In some cases, the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS);a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof. In some cases, ecDNA signature includes a detection or identification of ecDNA using an imaging technology. In some cases, ecDNA signature does not include any imaging or direct detection of ecDNA.

[0208] The term “selective ribonucleotide reductase inhibitor” or “selective RNR inhibitor” as used interchangeably herein, generally refers to inhibitors of ribonucleotide reductase (RNR) that specifically inhibit RNR without inhibiting other proteins or enzymes. In some cases, the selective RNR inhibitor is not a nucleoside analog. In some cases, the selective RNR inhibitor is not gemcitabine. In some cases, the selective RNR inhibitor is not hydroxyurea. In some cases, the selective RNR inhibitor has better (improved) selectivity for RNR inhibition as compared to gemcitabine and / or hydroxyurea.

[0209] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0210] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0211] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0212] “oxo” refers to =O.

[0213] “Amine” refers to -NH2;

[0214] “hydroxy” refers to -OH;

[0215] “Carboxyl” refers to -COOH.

[0216] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-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-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert- amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0217] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include all isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0218] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0219] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionallysubstituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0220] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0221] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0222] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclofl. l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro [3.3] heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0223] ‘ ‘Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0224] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, bromomethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2- fluoropropyl, 1,2-dibromoethyl, 1 -chloroethyl, and the like.

[0225] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0226] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. In some embodiments, 1-hydroxyeth-l-yl and 2-hydroxy-prop-2-yl, 2-hydroxy-2-methylprop-l-yl, or 2,3 -dihydroxypropyl.“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0227] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In oneaspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, - CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2C(CH3)2OCH3, -CH2NHCH3, -CH2N(CH3)2, - CH(CH3)N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0228] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. In some embodiments, the heterocycloalkyl comprises one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 folly saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 folly saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0229] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may includefused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxadiazolonyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0230] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, - CFHCHF2, etc ).

[0231] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, thesubject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.EXAMPLES

[0232] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.Example A: KRAS inhibition and ecDNA amplification

[0233] Mice were implanted with CT26WT E3 G12C KRAS mutant tumor cells. Once tumors reached an average volume of 350 mm3, mice were started on vehicle only or the KRAS inhibitor (KRASi) adagrasib at 50 mg / kg orally once per day. Tumor growth over the course of the treatment is shown in FIG. 1. As a single agent, the KRASi resulted in a significant delay in tumor growth. However, at about day 14, the tumors began to exhibit resistance to the inhibitor and tumor growth resumed.

[0234] To measure ecDNA, metaphase spreads were prepared from ex vivo cultures established from tumors taken from the mice on the day of sacrifice. ecDNA counts were determined using FISH for murine KRAS and quantified by manual counts. As shown in FIG. 2, no KRAS amplified ecDNA was seen in vehicle treated or untreated tumors. In comparison, tumors that developed resistance to KRASi were associated with high levels of KRAS ecDNA at termination. Imaging of the FISH samples confirmed that the KRAS was amplified on ecDNA.Example B: Synthetic Lethality of Compound 1 and KRAS inhibition

[0235] Mice were implanted with CT26WT E3 G12C KRAS mutant tumor cells. Once tumors reached an average volume of 350 mm3, mice were started on one of the following therapeutic regimens using the KRAS inhibitor (KRASi) adagrasib and / or Compound 1: (1) vehicle only; (2) KRASi at 50 mg / kg orally once per day; (3) Compound 1 at 150 mg / kg subcutaneously every other day; or (4) Compound 1 at 150 mg / kg subcutaneously every other day + KRASi at 50 mg / kg orally once per day.

[0236] Tumor growth in each of the treatments is shown in FIG. 3. As a single agent, only KRASi resulted in a significant delay in tumor growth. However, approximately two weeks into treatment, the tumors began to exhibit resistance to the KRASi and tumor growth resumed. When the KRASi was combined with Compound 1, tumor growth was inhibited and the inhibition continued through study day 29, the last day of the study.

[0237] In a model of adagrasib resistance enabled by KRAS containing ecDNA, mice were implanted with CT26WT E3 G12C KRAS mutant adagrasib resistant ecDNA+ tumor cells. The day after implant, all mice were treated with the KRAS inhibitor (KRASi) adagrasib at 50 mg / kg orally once per day to maintain ecDNA. Once tumors reached an average volume of -150 mm3, mice were started on one of the following therapeutic regimens using KRAS inhibitor and / or Compound 1: (1) vehicle only; (2) KRASi at 50 mg / kg orally once per day; (3) Compound 1 at 50 mg / kg subcutaneously twice every other day; or (4) Compound 1 at 50 mg / kg subcutaneously twice every other day + KRASi at 50 mg / kg orally once per day.

[0238] Results are shown in FIG. 4. As a single agent, the KRASi did not result in any delay in tumor growth demonstrating the adagrasib resistance. However, Compound 1 either as a single agent or when combined with the KRASi resulted in significant tumor growth inhibition (>90%) on study day 12. Mean tumor volume for Compound 1 treatments did not reach 500 mm3for all remaining tumors by Study Day 26, the last day of the study.Example C: Synthetic Lethality of Compound 1 and BRAF / EGFR inhibition

[0239] Mice were implanted with WiDr V600E BRAF mutant tumor cells. Once tumors reached an average volume of -160 mm3, mice were started on one of the following therapeutic regimens using the EGFR antibody (cetuximab) and the BRAF inhibitor (encorafenib) and / or Compound 1: (1) vehicle only; (2) EGFR antibody at 20 mg / kg intraperitoneally twice per week and BRAFi at 20 mg / kg orally once per day; (3) Compound 1 at 30 mg / kg subcutaneously twice every other day; or (4) Compound 1 at 30 mg / kg subcutaneously twice every other day + EGFR antibody at 20 mg / kg intraperitoneally twice per week + BRAFi at 20 mg / kg orally once per day.

[0240] Results of tumor growth for each of the treatments is shown in FIG. 5. As a double combination, EGFR antibody + BRAFi resulted in a significant delay in tumor growth for approximately 10 days; however, over the course of the study, the tumors began to exhibit resistance to the combination and continued to grow. The median time for tumors in the double combination group to reach a tumor volume of 500 mm3was 43 days. With the addition of Compound 1 to the EGFR antibody + BRAFi combination, a significant increase on tumor growth inhibition was observed. None of the tumors in this treatment group (all 3 agents) reached a tumor volume of 500 mm3at the end of study (Day 52), whereas the double combination, as well as the other treatment groups all exhibited tumor volumes greater than 500 mm3over the course of the study (FIG. 6A). As shown in FIG. 6B, all treatments in this study were well tolerated for entirety of the study.Example D: Synthetic lethality of Compound 1 and pan-FGFR inhibition

[0241] Mice were implanted with SNU-16 FGFR2 ecDNA+ tumor cells. Once tumors reached an average volume of -320 mm3, mice were started on one of the following therapeutic regimens using the FGFR inhibitor (infigratinib) and / or Compound 1: (1) vehicle only; (2) FGFRi at 15 mg / kg orally once per day; (3) Compound 1 at 30 mg / kg subcutaneously twice every other day, two weeks on / one weekoff; or (4) Compound 1 at 30 mg / kg subcutaneously twice every other day, two weeks on / one week off + FGFRi at 15 mg / kg orally once per day.

[0242] Results of tumor growth for each of the treatments is shown in FIG.7. As a single agent, FGFRi resulted in slight tumor regressions for approximately 10 days; however, over the course of the study, the tumors began to exhibit resistance and resumed growth. With the addition of Compound 1 to FGFRi, tumors regressed as on FGFRi alone; however, the mean tumor remained smaller than initial tumor volume for the duration of the study and a significant difference in mean tumor volume was observed at the end of study on Study Day 38. Example E: RNR Enzyme Activity

[0243] A rapid-fire mass spectrometry (RF / MS) assay was used to assess RNR enzyme activity using a 384 well plate and a robotic platform.

[0244] The plate layout included two validated reference compounds (Triapine (3-AP) and Hydroxyurea (HU)): • A dose response in duplicate; top concentration: 5µM (3-AP) and 250 µM (HU), semi-log dilutions. • Spike wells in triplicate randomly spotted at four concentrations: o 250 µM, 100 µM, 30 µM and 2 µM for HU o 5 µM, 2 µM, 0.6 µM and 0.04 µM for 3-AP

[0245] First, the multidrop pipes were saturated for 30 minutes with enzymatic solution. Then 30 µL of Stop solution was distributed in column 24. Next, 15 µL of enzyme was distributed in column 1 to 24. Next, a pre-incubation step of 15 minutes at room temperature occurred, followed by distribution of 15 µL of substrate solution (column 1 to 24). Next, the plate was incubated for 45 minutes at 37°C.30µL of Stop solution was distributed to columns 1 to 23.

[0246] The final parameters for the enzyme reactions were: • Incubation: 37°C, 45 min • [CDP]: 5 µM; [ATP]: 1 mM; [NADPH]: No • [RNR]final: 50 nM with 1:1 (RNR1:RNR2) ratio • Final volume: 30 µL • Stop solution: 6% HCOOH containing 2 µM of 15

[0247] The compounds (from Tables 2 and 3) were screened at concentrations up to 50 μM concentrations and the results are shown in Table 4 and Table 5.-83-Example F: Compound 1 treatment results in loss of ecDNA amplifications

[0248] SNU16 ecDNA+ cells were treated with Compound 1 at the IC50 and IC90 concentrations of 1.6uM and 2.4 uM for 15 days. Cell viability was measured by a cell-death and viability assessment using Trypan Blue staining. Results are shown in FIG. 8A. The treatments with Compound 1 led to a decline in cell viability. A FISH based cytogenetic analysis of MYC and FGFR2 DNA of the SNU16 cells treated for 7 days at the IC90 concentration of Compound 1 showed a reduction in FGFR2 and MY C ecDNA levels as compared to the vehicle treated control. Results are shown in FIG. 8B. Quantification of FISH signals for both FGFR2 and MYC was performed using ImageJ (Tool, Find maxima), and the results are shown in FIG. 8C and FIG. 8D. These results illustrated significant loss of ecDNA counts harboring the amplified oncogenes in a dose-dependent manner (pO.OOOl and p=0.0004, respectively). Biomarkers for replication stress, DNA damage and cell death protein biomarkers in the Compound 1 treated and vehicle treated cells were assayed by western blotting and results are shown in FIG. 8E. SNU16 cells at both IC50 and IC90 concentrations of Compound 1 showed a reduction in ecDNA cargo oncoprotein expression of FGFR2 and, its post-translationally modified form pFGFR-T653 / 654, concomitant with elevated expression of replication stress, DNA-damage and cell death marker, including pCHKl-S345, gH2AX-S139, and cleaved-caspase 3-D175 (FIG. 8E). However, reduction in ecDNA cargo oncoprotein expression of MYC was only observed at IC90 dose (FIG. 8E).Example G Compound 1 prevents ecDNA-mediated resistance associated with KRASG12Cinhibitor

[0249] Colorectal cancer non amplified CT26 cells were engineered to express the G12C allele of KRAS (CT26WT E3). The cells were then treated with adagrasib in a dose -dependent manner over weeks that led to acquired resistance to adagrasib mediated through the development of KRASG12C containing ecDNA as shown by FISH analysis (FIG. 9A). Resistance to adagrasib in this cell line was confirmed using a 5 -day cell proliferation assay. As shown in FIG. 9B, adagrasib treatment of the parental, CT26SM5G72Gnon-amplified retained sensitivity to the compound, whereas theecDNA+KRASG12C amplified cells exhibited resistance to adagrasib. Activation of the KRAS and the flux through the KRAS pathway was assessed using western blotting. The CT26SM5G72GecDNA+ KRASG12C amplified cells were found to harbor KRASG12C amplifications on the ecDNA in concomitance with the baseline activation of the MAPK signaling as shown by western blotting of relevant biomarkers (FIG. 9C). A qPCR analysis was performed to assess KRASG12C gene copy number.Example H: Compound 1 delays the development of resistance to adagrasib in vivo

[0250] Mice were implanted with CT26WT E3 G12C KRAS mutant tumor cells. Once tumors reached an average volume of 350 mm3 , mice were started on one of the following therapeutic regimens usingKRAS inhibitor (adagrasib) and / or Compound 1: (1) vehicle only; (2) KRASi (adagrasib) at 50 mg / kg orally once per day (PO QD); (3) Compound 1 at 50 mg / kg subcutaneously twice every other day (SC BID Q2D); or (4) Compound 1 at 50 mg / kg subcutaneously twice every other day (SC BID Q2D) + KRASi (adagrasib) at 50 mg / kg orally once per day (PO QD). Results are shown in FIG. 10A. As a single agent, adagrasib resulted in a significant delay in tumor growth. However, approximately two weeks into treatment, the tumors began to exhibit resistance and tumor growth resumed. In association with this regrowth, qPCR analysis of genomic DNA isolated from tumors at termination demonstrated a significant increase in Kras gene copy number. When Compound 1 was combined with adagrasib, tumor growth was inhibited and continued through study day 85, the last day of dosing the study (FIGS. 10A and 10B). The Kras gene copy number determined in terminal tumors from the combination group demonstrated that Compound 1 abrogated adagrasib-mediated Kras amplification in resistant tumors (FIG. 10C).Example I: Compound 1 delays acquired resistance to treatment of MRTX1133 in Ct26A'"'4'l2l)CRC cells in vitro by arresting KRAS amplifications

[0251] In vitro antiproliferation activity of Compound 1 in combination with MRTX1133 in Ct26&“’’G12Dcolorectal cells. For this study, Ct26&as G12Dcolorectal cells were treated with increasing drug doses of MRTX1 133 alone and / or in combination with consistent dose of Compound 1 at luM (IC10) and / or at 1.5uM (IC50) used throughout the dose escalation period of 8 weeks. At week 1, the starting concentration of MRTX1133 was 50nM (IC10). At the end of 3 weeks the concentration of MRTX1133 was increased to a final concentration of luM and cells were maintained at that concentration until the end of week 8 (FIG. 11A). Cell counts were measured at every cycle of cell splitting which was approximately every 1-2 weeks. CT26 / ;'a'J’: l 2l JCRC cells treated with increasing doses of MRTX1133 developed acquired resistance to KRASG12Di by driving KRAS amplifications on ecDNA (FIG. 1 IB). MRTX1133 alone led to a significant antiproliferation activity when compared to vehicle treated cells (p<0.0005), however there was progressive increase in tumor cell proliferation. In contrast, combination treatment of MRTX1 133 + Compound 1 at both luM (IC10) and / or at 1.5uM (IC50) led to a significant antiproliferation activity when compared to MRTX1133 only treated cells (p=0.0181 and p=0.0032, respectively) concomitant with suppression of resistance mediated KRAS amplifications (FIG. 11C).

[0252] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only.

[0253] Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of delaying or preventing resistance to a therapeutic agent in a subject in need thereof comprising administering a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject, wherein the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and / or a receptor tyrosine kinase (RTK) inhibitor, and wherein the method results in a delay or prevention of resistance by a tumor or tumor cells to the therapeutic agent.

2. A method of treating cancer in a subject in need thereof comprising administering a selective ribonucleotide reductase (RNR) inhibitor and a therapeutic agent to the subject, wherein the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and / or a receptor tyrosine kinase (RTK) inhibitor.

3. The method of claim 1 or claim 2, wherein the method results in the inhibition of growth of the tumor or proliferation of the tumor cells.

4. A method of treating a subject having a tumor or tumor cells resistant to a therapeutic agent comprising administering a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject, wherein the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and / or a receptor tyrosine kinase (RTK) inhibitor, wherein the subject has been previously treated with the therapeutic agent and demonstrated decreased responsiveness or resistance to the therapeutic agent, and wherein the method results in inhibition of growth of the tumor or proliferation of the tumor cells.

5. The method of any one of claims 1 to 4, wherein the therapeutic agent comprises one or more inhibitors.

6. The method of any one of claims 1 to 4, wherein the therapeutic agent comprises at least two inhibitors.

7. The method of any one of claims 1 to 6, wherein the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR / MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a SOS1 inhibitor.

8. The method of any one of claims 1 to 7, wherein the therapeutic agent comprises a BRAF inhibitor and a second inhibitor.

9. The method of claim 8, wherein the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor.

10. The method of any one of claims 1 to 7, wherein the therapeutic agent comprises a KRAS inhibitor and a second inhibitor.

11. The method of claim 10, wherein the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an SOS1 inhibitor.

12. The method of any one of claims 2 to 11, wherein inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone.

13. The method of any one of claims 1 to 12, wherein the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.

14. The method of any one of claims 1 to 13, wherein the therapeutic agent and the RNR inhibitor are administered concurrently.

15. The method of any one of claims 1 to 13, wherein the therapeutic agent and the RNR inhibitor are administered sequentially.

16. The method of any one of claims 1 to 15, wherein the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.

17. The method of any one of claims 1 to 16, wherein the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.

18. The method of claim 17, wherein the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.

19. The method of any one of claims 1 to 18, wherein the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene.

20. The method of claim 19, wherein the focal amplification is less than 20 Mb.

21. The method of any one of claims 1 to 20, wherein the tumor or tumor cells comprise an ecDNA signature.

22. The method of any one of claims 1 to 21, wherein the tumor or tumor cells are ecDNA competent.

23. The method of any one of claims 19 to 22, wherein the focal amplification is comprised on ecDNA.

24. The method of any one of claims 1 to 23, wherein the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRASG12C, KRASG12V, or a KRASG12Dmutation.

25. The method of claim 24, wherein the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.

26. The method of claim 25, wherein the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI- 421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF- 105, GH-35, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC- 6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.

27. The method of any one of claims 1 to 23, wherein the therapeutic agent comprises a BRAF inhibitor, and the tumor or tumor cells comprise a BRAFV600Emutation.

28. The method of claim 27, wherein the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.

29. The method of claim 28, wherein the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.

30. The method of any one of claims 1 to 29, wherein the RNR inhibitor is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

31. The method of any one of claims 1 to 29, wherein the RNR inhibitor is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

32. The method of any one of claims 1 to 29, wherein the RNR inhibitor is TAS1553.

33. The method of any one of claims 1 to 32, wherein the method further comprises administering an EGFR inhibitor.

34. The method of claim 33, wherein the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS- 2087, DZD-9008, E01001, E-10C, epertinib, epitinib (HMPL-813), erlotinib, ES-072, FCN-411, FHND- 9041, furmonertinib, FWD-1509, GB-263, GC-1118A, gefitinib, GMA-204, GR-1401, Hemay-022, HLX- 07, HS-627, 1-010, icotinib, imgatuzumab, IN-A008, JMT-101, JRF-103, JS-111, JS-113, JZB-28, KN- 023, KN-026, KP-673, lapatinib, larotinib, lazertinib, LL-191, LYN 205, maihuatinib, marizomib, mobocertinib, MP-0274, naputinib tosilate, nazartinib, necitumumab, neptinib, nimotuzumab, NRC-2694- A, NT-004, OBX1-012, olafertinib, olmutinib, ORIC-114, oritinib, osimertinib, panitumumab, pirotinib, poziotinib, PRB-001, pyrotinib, QL-1203, SCT-200, serclutamab, SHR-A1307, SIM-200, SPH-1188, SSGJ-612, SYN-004, TAD-011, tarloxotinib, TAS-6417, TGRX-360, theliatinib (HMPL-309), TPC-064, TQB-3804, TY-9591, WJ-13404, WSD-0922, XZP-5809, yinlitinib maleate, YK-029A, YZJ-0318, zorifertinib, ZSP-0391, and combinations thereof.

35. The method of any one of claims 1 to 34, wherein prior to administration of the RNR inhibitor, the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.

36. The method of claim 35, wherein the mutation is BRAFV600E,KRASG12C, KRASG12V, or KRASG12D.

37. The method of claim 35 or claim 36, wherein the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.

38. The method of any one of claims 35 to 37, wherein the amplification of the RTK or MAPK gene is detected by NGS.

39. A method of treating a tumor or tumor cells in a subject that are resistant to a therapeutic agent, comprising administering a selective ribonucleotide reductase (RNR) inhibitor to the subject, wherein the tumor or tumor cells comprise a focal amplification of a mitogen activated protein kinase (MAPK) pathway gene or a receptor tyrosine kinase (RTK) gene, wherein the therapeutic agent targets the MAPK pathway gene or the RTK gene, and where the method results in inhibition of growth of the tumor or proliferation of the tumor cells.

40. The method of claim 39, wherein the therapeutic agent targets KRAS.

41. The method of claim 39, wherein the therapeutic agent targets KRASG12C, KRASG12V, or KRASG12D.

42. The method of any one of claims 39 to 41, wherein the focal amplification is comprised on ecDNA.

43. The method of any one of claims 39 to 42, wherein the therapeutic agent is a KRAS inhibitor.

44. The method of claim 43, wherein the KRAS inhibitor is selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI- 2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.

45. The method of any one of claims 39 to 44, wherein the RNR inhibitor is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

46. The method of any one of claims 39 to 44, wherein the RNR inhibitor is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

47. The method of any one of claims 39 to 44, wherein the RNR inhibitor is TAS 1553.

48. The method of any one of claims 39 to 46, wherein the copy number of one or more oncogenes associated with the focal amplification is reduced after administering the selective RNR inhibitor.

49. The method of any one of claims 1 to 38, wherein the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.

50. A method of treating a tumor or tumor cells comprising administering a selective ribonucleotide reductase (RNR) inhibitor, wherein the tumor cells comprise ecDNA-derived amplification of an oncogene, and wherein the treatment reduced the level of amplification of the oncogene.

51. The method of claim 50, wherein the size of the tumor or growth of the tumor or growth of the tumor cells is inhibited after treatment with the selective RNR inhibitor.

52. The method of claim 50 or claim 51, wherein the focal amplification is comprised on ecDNA.

53. The method of any one of claims 50-52, wherein the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

54. The method of any one of claims 50-52, wherein the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

55. The method of any one of claims 50-52, wherein the RNR inhibitor is TAS1553.

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