WO2024091409A1

WO2024091409A1 - Tricyclic derivatives as kras inhibitors

Info

Publication number: WO2024091409A1
Application number: PCT/US2023/035389
Authority: WO
Inventors: Jiping Fu
Original assignee: Nikang Therapeutics, Inc.
Priority date: 2022-10-24
Filing date: 2023-10-18
Publication date: 2024-05-02

Abstract

The present disclosure provides certain tetracyclic derivatives that inhibit certain K-Ras proteins and are therefore useful for the treatment of cancers mediated by such proteins. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

TRICYCLIC DERIVATIVES AS KRAS INHIBITORS

Related Applications

This application claims priority to, and the benefit of, US Provisional Application No. 63/380,674, filed on October 24, 2022, the content of which is incorporated herein by reference in its entirety.

Field of the disclosure

Background

Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) gene is a prevalent oncogene that encodes a small GTPase transductor protein called K-Ras. K-Ras can serve as a molecular switch by cyling between active GTP -bound and inactive GDP-bound forms (see Science 2001;294: 1299-304.). K-Ras signaling is activated by RAS guanine nucleotide exchange factors (GEFs), e.g., Son of Sevenless homologue (SOS) protein, that facilitate the GDP to GTP exchange of K-Ras (see Curr Biol 2005;15:563-74.). The interaction between K-Ras and GTPase-activating proteins (GAPs) such as pl20GAP and neurofibromin, potentiates K-Ras intrinsic GTPase activity and accelerates GTP hydrolysis and diminishing K-Ras signaling (see Curr. Biol. 2005;15:563-74.).

K-Ras plays a crucial role in the regulation of cell proliferation, differentiation and survival by signaling through several major downstream pathways, including the MAPK, the PI3K and the Ral-GEFs pathways (see Lung Cancer 2018;124: 53-64), among them the MAPK pathway is the best characterized (see Mol. Cell Biol.1995;15:6443-6453.). K- Ras-GTP binds to and activates RAF kinases, which phosphorylates MEK and subsequently phosphorylates ERK. Phospho-ERK can further activate downstream cytosolic proteins and which then translocate to the nucleus to drive the expression of diverse genes, propagating the growth signal. PI3K pathway is also involved in RAS-mediated tumorigenesis (see Cell 2007;129:957-968.). Upon activation by K-Ras-GTP, PI3K phosphorylates PIP2 to form PIP3, activates PDK1 and then phosphorylates AKT. pAKT yields phosphorylation of several physiological substrates, e.g., mTOR, FOXO and NF-KB that promote metabolism, cell-cycle progression, resistance to apoptosis, cell survival and migration. The Ral-GEFs signaling pathway plays a key role in RAS-mediated oncogenesis as well (see Proc. Natl. Acad. Sci. U. S. A. 1994; 91 : 11089-11093.). The K-Ras effector, RALGDS, stimulates the RAS family RAL-A/B small GTPases for the subsequent signaling cascades. RALGDS can also promote the JNK pathway to stimulate transcription of pro-survival and cell-cycle progression genes for cell proliferation and survival.

KRAS gene is the most frequently mutated oncogene in human cancer. KRAS mutations are associated with poor clinical outcome and found at high frequency in pancreatic cancer (-90%), colorectal cancer (~44%) and non-small-cell lung cancer (NSCLC) (~29%) (see Cancer Discov. 2021;11 : 1-16). KRAS mutations are also present in breast cancer, liver cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer and myeloid leukemia. The most common KRAS mutations are observed at residues G12 (77%), G13 (10%), and Q61 (6%), and the most predominant KRAS variant in human malignancies is G12D (35%), followed by G12V (29%), G12C (21%), G12A (7%), G12R (5%), and G12S (3%) (see Cancer Discov. 2021; 11 : 1-16). These mutations perturbate GTP hydrolysis of K-Ras by interfering with GAP binding/stimulation and/or reducing K-Ras intrinsic GTPase activity, resulting in constitutive activation of the protein and K-Ras signaling.

Targeting KRAS signaling has been a long pursuit in drug discovery. Among KRAS mutants, K-Ras G12C offers special opportunity, because it harbors a non-native cysteine residue, which can act as nucleophile and therefore can be targeted by covelent attachment. Besides AMG510, which is an approved drug for treating K-Ras G12C driven cancers, several other K-Ras G12C covelent inhibitors, including MRTX849, JNJ- 74699157 and LY349944631, are in clinical trials for treating cancer patients with KRAS G12C mutation (see ACS Cent. Sci. 2020;6: 1753-1761). Compared to K-ras G12C mutant, other prevalent K-Ras mutants, such as G12V, do not contain non-native cysteine residue, thus making non-G12C mutant-specific drug discovery more challenging. Given the role of K-Ras mutants in human malignancy, there is still unmet medical need for development of new treatments for cancer patients with KRAS mutations. The present disclosure fulfills this and related needs.

Summary

In a first aspect, provided is a compound of Formula (I):

wherein:

X is N or CH;

Z¹ is CH₂, O, S or NH; m is 1, 2, or 3 when Z¹ is O, S or NH; and m is 0, 1, or 2, when Z¹ is CH₂; q is 0, 1, 2, 3;

R^la is hydrogen, deuterium, alkyl, alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, cyanomethyl, or cyanoethyl;

R^lb, R^lc, and R^ld are independently selected from hydrogen, halo, oxo, and alkyl; or when R^la and R^lb are attached to the same carbon of the ring, they can combine to form cycloalkylene optionally substituted with alkyl, halo, alkoxy, cyano, or hydroxy;

R¹ is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano provided that R¹ is absent when X is N;

R² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, alkenyl, alkynyl, or cyano;

R³ is -Y-R⁶ where Y is a bond, O, NH, N(alkyl), or S; and R⁶ is heterocyclylalkyl, fused heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, heterocyclyl fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein:

(1) fused heterocyclyl of fused heterocyclylalkyl is substituted with R^a, R^b, R^c, and R^C1 where R^a is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylidene, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR⁷R⁸ and the alkyl portion of fused heterocyclylalkyl is optionally substituted with one or two deuterium;

(2) heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, are substituted with R^d, R^e, R^f, and R^fl where R^d is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylidene, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR⁹R¹⁰ and the alkyl portion of heterocyclylalkyl and bicyclic heterocyclylalkyl is optionally substituted with one or two deuterium;

(3) fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, by itself or as part of heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl, are independently substituted with R^g, R^h, R¹, and R¹¹ where R^s is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylidene, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CRⁿR¹² and the alkyl portion of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl is optionally substituted with one or two deuterium;

R⁷, R⁹, and R¹¹ are independently hydrogen, deuterium, alkyl, halo, or haloalkyl;

R⁸, R¹⁰, and R¹² are independently hydrogen, alkyl, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl, phenyl, or heteroaryl; or independently of each other, R⁷ and R⁸, R⁹ andR¹⁰, and R¹¹ and R¹² together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;

R^b, R^e, and R^h are -(Q¹)_ni-OC(O)NR¹³R¹⁴ (wherein nl is 0 or 1; Q¹ is alkylene or deuterioalkylene, R¹³ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl, and R¹⁴ is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl substituted with R¹ and R^k independently selected from hydrogen, alkyl, halo, alkoxy, haloalkyl, and haloalkoxy; or R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl wherein (a) the heterocyclyl formed together by R¹³ and R¹⁴ is substituted with R^m, Rⁿ, R°, and R^p where R^m and Rⁿ are independently selected from hydrogen, deuterium, alkyl, alkoxylalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy, alkoxyalkoxy, and hydroxy; R° is hydrogen, deuterium, alkylidenyl, deuterioalkylidenyl, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R^p is hydrogen, deuterium, or fluoro and (b) the bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl formed together by R¹³ and R¹⁴ are independently substituted with R^q, R^r, and R^s independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy; or - (Q²)-OR^13a (wherein Q² is alkylene or deuterioalkylene, R^13a is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl (wherein each ring of R^13a , by itself or as part of another group, is substituted with R R^u, and R^v independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile));

R^c, R^f, and R¹ are independently hydrogen, deuterium, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy;

R^cl, R^fl, and R¹¹ are independently selected from hydrogen, deuterium, alkyl, and halo; and

R⁴ is -Q-R¹⁵ where Q is bond, alkylene, or -C(=O)-; and R¹⁵ is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, aralkyl, heteroaryl, fused heteroaryl, or heteroaralkyl wherein aryl, aryl in aralkyl, heteroaryl, fused heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^ddis hydrogen, alkyl, alkylthio, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

L is a bond, alkylene, cycloalkylene, or heterocyclylene , where alkylene, cycloalkylene, and heterocyclylene are substituted with R¹⁶ selected from hydrogen, halo, alkyl, haloalkyl, hydroxy, cycloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, heterocyclyl, oxo, amino, alkylamino, or dialkylamino;

R⁵ is hydrogen, cycloalkyl, aryl, fused cycloalkyl, heteroaryl, heterocyclyl, or fused heterocyclyl, wherein cycloalkyl, aryl, heteroaryl, fused cycloalkyl, heterocyclyl, and fused heterocyclyl are substituted with R¹⁷, R¹⁸, and R¹⁹ independently selected from hydrogen, alkyl, alkoxylalkyl, halo, haloalkyl, oxo, CN, 0R^ee, -S(O)_nR^ff, -C(0)NR^ssR^bh, - OC(O)NR"R¹¹, and 'NR^kkR^mm where R^ee, R^gg, R^, R", R^jj, R^kk, and R^mm are indendently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or alkoxylalkyl; and R^ff is alkyl, haloalkyl, cycloalkyl, heteroalkyl, or alkoxylalkyl; or a pharmaceutically acceptable salt thereof.

In a second aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In a third aspect, provided is a method of inhibiting K-Ras, in particular K-Ras G12V, in a cell, comprising contacting the cell with a compound of Formula (I) (or any of the embodiments thereof described herein). In one embodiment of the third aspect, the contacting is in vitro. In another embodiment of the third aspect, the contacting is in vivo.

In a fourth aspect, provided is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutical composition thereof as disclosed herein. In one embodiment of the fourth aspect, the contacting is in vitro. In another embodiment of the fourth aspect, the contacting is in vivo.

In a fifth aspect, provided is a method of treating cancer in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.

In a sixth aspect, provided is a method of treating cancer associated with K-Ras, in particular K-Ras G12V, in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.

In a seventh aspect, provided is a compound of Formula (I), (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a medicament. In one embodiment, the medicament is useful for the treatment of cancer. In an eighth aspect, provided is a compound of Formula (I), (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a therapy.

In a ninth aspect, provided is a compound of Formula (I), (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancer.

In a tenth aspect, provided is a compound of Formula (I), (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancers associated with KRas, in particular cancers associated with K-Ras G12V.

In an eleventh aspect, provided is a compound of Formula (I), (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in inhibiting K-Ras, in particular K-Ras G12V.

In any of the aforementioned aspects involving the treatment of cancer, are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially.

Detailed Description

Definitions:

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:

“Alkyl” means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atomsunless stated otherwise, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

“Alkylene” means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1- methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

“Alkenyl” means a linear or branced monovalent hydrocarbon radical of two to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like. “Alkynyl” means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.

“Amino” means -NH2.

“Alkylamino” means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, and the like.

“Alkylthio” means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.

“Alkyl sulfonyl” means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethyl sulfonyl, and the like.

“Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2 -methoxy ethyl, 1-, 2-, or 3 -methoxypropyl, 2-eth oxyethyl, and the like.

“Alkoxyalkyloxy” means a -OR radical where R is alkoxyalkyl as defined above, e.g., 2 -methoxy ethyl, 1-, 2-, or 3 -methoxypropyl, 2-ethoxyethyl, and the like.

“Alkylidenyl” means refers to a group of formula R= where R is alkyl as defined above. Examples include, but are not limited to, methylidenyl (H2C=), ethylidenyl (CH3CH=), hexylidenyl (CH3(CH2)4CH=), 2-propylidenyl (=C(CH3)2), and the like. For example, in the compound below:

the alkylidene group, methylidenyl, is enclosed by the box which is indicated by the arrow.

“Alkoxyalkylidenyl” means refers to a group of formula =R where R is alkoxyalkyl as defined above. Examples include, but are not limited to, methoxethylidenyl (CH₃OCH₂CH=), ethoxyethylidenyl (C₂H₅OCH₂CH=), 1- m ethoxy ethylidenyl (=C(CH3)OCH3), and the like. For example, in the compound below:

the alkoxyalkylidenyl group, methoxethylidenyl, is enclosed by the box which is indicated by the arrow.

“Alkylcarbonyl” means a -C(O)R radical where R is alkyl as defined above e.g., - C(O)CH3, and the like.

“Alkoxycarbonyl” means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxy carbonyl, ethoxycarbonyl, and the like.

“Amino” means a -NH2 radical.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Aralkyl” means a -(alkylene)-R radical where R is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.

“Bicyclic heterocyclyl” means a saturated monovalent fused bicyclic ring of 8 to 12 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term bicyclic heterocyclyl includes, but is not limited to, hexahydro- IH-pyrrolizinyl, and the like.

“Bicyclic heterocyclylalkyl” means a -(alkylene)-R radical where R is bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-lH- pyrrolizinylmethyl, hexahydro- IH-pyrrolizinyl ethyl, and the like.

“Bridged heterocyclyl” means a saturated bicyclic ring having 5 to 9 ring atoms in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring atoms, including the atoms of the bridging group, are heteroatoms independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2. Examples include, but are not limited to, 6-oxa-3- azabicyclo[3.1.1]heptane-3-yl8-oxa-3-azabicyclo[3.2.1]octane-3-yl, and the like. “Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“Cycloalkylene” means a monocyclic saturated divalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, 1,1- cyclopropylene,l,l- cyclobutylene, 1,1-cyclopentylene, and the like.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl cyclobutyl ethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

“Cycloalkyloxy” or “cycloalkoxy” means a -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyl oxy, cyclobutyl oxy, cyclopentyloxy, cyclohexyl oxy, and the like.

“Cyanoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like.

“Cyanoalkenyl” means an alkenyl radical as defined above where one of the hydrogen atom in the alkenyl chain is replace by a cyano. Examples include, but are not limited to, -C=C(CN), -CH₂C=C(CN), and the like.

“Cyanoalkynyl” means an alkynyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C=C(CN), -CH₂C=C(CN), and the like.

“Deuterium” mean refers to ²H or D.

“Deuterioalkyl” means alkyl as defined above that is substituted with one or two deuterium, e.g., CD₂, CHD, and the like.

“Deuterioalkylene” means alkylene as defined above that is substituted with one or two deuterium, e.g., CD₂, CHD, and the like.

“Deuterioalkylidenyl” means refers to a group of formula R= where R is deuterioalkyl as defined above. Examples include, but are not limited to, (D₂C=), ethylidenyl-2,2,2-d3 (CD3CH=), For example, in the compound below:

the alkylidene group, methylidenyl-d2, is enclosed by the box which is indicated by the arrow.

“Dialkylamino” means a -NRR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.

“Fused bicyclic heterocyclyl” means a saturated monovalent fused bicyclic ring of 8 to 10 ring atoms in which one or two ring atoms are heteroatoms independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, one ring atom can be - CO-, and the remaining ring atoms being C, unless stated otherwise, and where two adjacent ring atoms of the bicyclic ring are fused to two adjacent ring atoms of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. More specifically the term fused bicyclic heterocyclyl includes, but is not limited to, 2,3- dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl, 2,3-dihydro-lH-pyrrolo[l,2-a]indol- 9a(9H)-yl, l,3b,4,5,6,8-hexahydropyrrolo[3,2-a]pyrrolizin-3b-yl, and the like.

“Fused bicyclic heterocyclylalkyl” means a -(alkylene)-R radical where R is fused bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-lH-pyrrolizinylmethyl, hexahydro-lH-pyrrolizinyl ethyl, 2,3-dihydro-lH- pyrrolo[2,l-a]isoindol-9b(5H)-ylmethyl, 2,3-dihydro-lH-pyrrolo[l,2-a]indol-9a(9H)- ylmethyl, and the like.

“Fused cycloalkyl” as used herein, means cycloalkyl as defined above where two adjacent ring atoms of the cycloalkyl ring are fused to two adjacent ring atoms of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The fused cycloalkyl can be attached at any atom of the ring. Non limiting examples of the fused cycloalkyl include bicyclo[4.1.0]hepta-l,3,5-triene, bicyclo[4.2.0]octa-l,3,5-triene, and the like.

“Fused spirocycloalkyl” means spirocycloalkyl as defined herein where two adjacent ring atoms of the spiro cycloalkyl are fused to two adjacent ring atoms of a phenyl or a five or six membered heteroaryl, each as defined herein.

“Fused heterocyclyl” means a saturated monovalent monocyclic ring of 4 to 7 ring atoms having from one to three heteroatoms independently selected from N, O, and S(O) n where n is 0, one ring atoms can be -CO-, and the remaining ring atoms being carbon, and further wherein two adjacent ring atoms of the monocyclic ring are fused to two adjacent ring atoms of a cycloalkyl, phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom(s) are optionally oxidized optionally quaternized and one or two carbon atoms of the fused ring atoms in the saturated monocyclic ring includes the two common ring vertices shared with the fused phenyl or five or six membered heteroaryl. The fused heterocyclyl can be attached at any atom of the ring. Non limiting examples of the fused heterocycloalkyl include 2,3- dihydrobenzo[b][l,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexanyl, indolin-2-one-l-yl, indolinyl, and the like.

“Fused heterocyclylalkyl” as used herein, means a -(alkylene)-R radical where R is fused heterocyclyl, as defined herein.

“Fused heteroaryl” means fused bicyclic heteroaryl, as defined herein, where two adjacent ring atoms of the heteroaryl ring are fused to two adjacent ring atoms of phenyl.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

“Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, - CF2CF3,

-CF(CH₃)₂, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

“Haloalkylidenyl” means refers to a group of formula =R where R is haloalkyl as defined above. Examples include, but are not limited to, difluoromethylidenyl (=CF2), 2,2- difluoroethylidenyl (=CHCHF2), 1-fluoroethylidenyl =CFCH3), and the like. For example, in the compound below:

the group pointed to by the arrow is the haloalkylidenyl group, difluoromethylidenyl.

“Haloalkoxy” means a -OR radical where R is haloalkyl as defined above e.g., - OCF3,

-OCHF2, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.

“Haloalkoxyalkyl” means a -(alkylene)OR radical where R is haloalkyl as defined above, e.g., trifluoromethoxymethyl, difluoromethoxymethyl, and the like. “Haloalkylcarbonyl” means a -C(O)R radical where R is haloalkyl as defined above e.g., -C(O)CF3, -C(O)CHF2, and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3 -hydroxypropyl, 1- (hydroxymethyl)-2-m ethylpropyl, 2-hydroxybutyl, 3 -hydroxybutyl, 4 -hydroxybutyl, 2,3- dihydroxypropyl, 1 -(hydroxymethyl)-2 -hydroxy ethyl, 2,3 -dihydroxybutyl, 3,4- dihydroxybutyl and 2-(hydroxymethyl)-3 -hydroxypropyl, preferably 2 -hydroxy ethyl, 2,3- dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxy ethyl.

“Heteroalkyl” mean alkyl radical as defined above wherein one or two carbon atoms are replaced by O, NR (R is H or alkyl), or S, provided the heteroalkyl group is attached to the remainder of the molecule via a carbon atom, e.g., methoxymethyl, methylethylaminoethyl, and the like.

“Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5- or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl. When the heteroaryl ring is fused bicyclic aromatic radical 9- or 10 ring atoms it is also referred to herein as fused bicyclic heteroaryl.

“Heteroaralkyl” means a -(alkylene)-R radical where R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like. When the heteroaryl ring in heteroaralkyl contains 5- or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl.

“Heterocyclyl” means a saturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2- oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

Heterocyclylalkyl” or “heterocycloalkyl” means a -(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinyl ethyl, and the like.

“Heterocyclyl fused bicyclic heterocyclyl” means a bicyclic heterocyclyl as defined herein (preferably a bicyclic heterocyclyl of 8 to 10 ring atoms) where two adjacent ring atoms of the bicyclic heterocyclyl are fused to two adjacent ring atoms of a hetereocyclyl ring as defined herein, provided the heterocyclyl ring contains at least two ring heteroatoms independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2. The term heterocyclyl fused bicyclic heterocyclyl includes, but is not limited to,

the like.

“Heterocyclyl fused bicyclic heterocyclylalkyl” mean -(alkylene)-R where R is heterocyclyl fused bicyclic heterocyclyl as defined above.

“Heterocyclylene” means a saturated divalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise.

“Oxo,” as used herein, alone or in combination, refers to =(O).

“Optionally substituted aryl” means aryl as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano. When aryl is phenyl, optionally substituted aryl is referred to herein as optionally substituted phenyl. “Optionally substituted heteroaryl” means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

“Optionally substituted heterocyclyl” means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, alkylcarbonyl, hydroxyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated otherwise.

“Optionally substituted heterocyclyl alkyl” means -(alkylene)-R where R is optionally substituted heterocyclyl as defined above.

“Spirocycloalkyl” means a saturated bicyclic monovalent ring having 5 to 10 ring atoms in in which the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Unless stated otherwise, spiro cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]-nonane, and the like.

“Spiro heterocyclyl” means a saturated monovalent bicyclic ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Representative examples include, but are not limited to, 2,6-diazaspiro-[3.3]heptanyl, 2,2-dioxido-2- thiaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 2- azaspiro[3.5]-nonanyl, 2,7-diazaspiro[4.4]nonanyl, and the like.

“Tricyclic heterocyclyl” means a saturated monovalent fused tricyclic ring of 9 to 14, preferably 12 to 14, ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)_n, where n is an integer from 0 to 2, one ring atom can be -CO-, and the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. The term tricyclic heterocyclyl includes, but is not limited to,

, and the like.

“Tricyclic heterocyclylalkyl” means a -(alkyl ene)-R radical where R is tricyclic heterocyclyl as defined above. Examples include, but are not limited to,

the like.

The present disclosure also includes protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5^th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

The present disclosu^re also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-l -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, A-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ’s Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

The compounds of Formula (I) may have asymmetric centers. Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as I stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa.

Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) are within the scope of this disclosure.

The compounds of Formula (I) may also conta- 18 -nnaturalural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question, that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵ S, ¹⁸F, ³⁶C1, ¹²³I, and ¹²⁵1, respectively. Isotopically labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of Formula (I), including in Table 1 below one or more hydrogen atoms are replaced by ²H or ³H, or one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ⁿC, and ¹⁵F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.

“A pharmaceutically acceptable carrier/excipien ’ as used in the specification and claims includes both one and more than one such excipient.

The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean the recited value ± lOof the recited value, preferably the recited value ± 5% of the recited value, the recited value and the range is included”.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, optionally substituted aryl substituted with alkyl is intended to cover aryl that is unsubstituted and aryl that is substituted with alkyl.

Certain structures provided herein are drawn with one or more floating substituents (i.e., they are not bonded to a particular atom of a ring in the Markush structure). Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any atom of the ring through which they are drawn, where chemically feasible and valency rules permitting. For example, in the structure of Formula (I):

R¹ and R² groups are floating substituents and can replace any unsubstitued carbon atom of the

portion of the depicted ring, including when X is CH recited in the structure of Formula (I) (and any embodinments thereof defined herein), valency permitting.

Similarly, Rl^a, R^lb, Rl^c,and R^ld groups are floating substituents and can replace any unsubstitued carbon atom of ring of the ring through which they are drawn

Formula (I), including when Z¹ is CH2 (one of both hydrogen atoms of CH2 can be replaced by Rl^a, R^lb, Rl^c,and R^ld) or NH.

The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;

(2) inhibiting the disease, i.e., delaying, arresting (i.e., stabilizing), or reducing the development or severity of the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

In one embodiment, treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. The therapeutically effective amount of a K-ras inhibitor disclosed herein can be administered to the patient in a single dosage form or multiples thereof. For example, 600 mg dose of a K-ras inhibitor can be administered in a single 600 mg tablet or two 300 mg tablets.

The terms "inhibiting" and "reducing," or any variation of these terms in relation of K-Ras G12V, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of K- Ras G12V GTPase activity; a decrease of K-Ras G12V GTP binding affinity or an increase of G12V GDP binding affinity; an increase of GTP off rate or a decrease of GDP off rate; a decrease of signaling transduction molecules levels downstream in the K-Ras pathway, e.g., a decrease in pERK level; and/or a decrease of K-Ras complex binding to downstream signaling molecules compared to normal. Representative compounds of Formula (I) are disclosed in Compound Table 1 below:

Representative contemplated compounds of Formula (I) are disclosed in

Compound Table 1 A below:

Table 1A

Embodiment A:

In further embodiments 1-189 below, the present disclosure includes:

1. In embodiment 1, provided is a compound of Formula (I) as defined in the first aspect of the Summary, or a pharmaceutically acceptable salt thereof.

2. In embodiment 2, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I) is according to structure (la):

(la).

3. In embodiment 3, the compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I) is according to structure (lai):

4. In embodiment 4, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I) is according to structure (Ia2):

5. In embodiment 5, the compound of embodiment 1 or 4, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I) is according to structure (lb):

(lb).

6. In embodiment 6, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I) is according to structure (Ic):

(Ic).

7. In embodiment 7, the compound of embodiment 1 or 6, or a pharmaceutically acceptable salt thereof, is wherein the compound of Formula (I) is according to structure (Id):

(Id).

8. In embodiment 8, the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is fused heterocyclylalkyl where fused heterocyclyl of fused heterocyclylalkyl is substituted with R^a, R^b, R^c and R^C1 as defined in the Summary.

9. In embodiment 9, the compound of any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclyl of fused heterocyclylalkyl of R⁶ is isoindolinyl substituted with R^a, R^b, R^c and R^C1 as defined therein.

10. In embodiment 10, the compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, is wherein R^ais alkylidene.

11. In embodiment 11, the compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, is wherein R^ais deuterioalkylidenyl.

12. In embodiment 12, the compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, is wherein R^ais methylidene or methylidene-d2.

13. In embodiment 13, the compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, is wherein R^ais haloalkylidenyl.

14. In embodiment 14, the compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclylalkyl of R⁶ is a ring of formula:

are as defined therein and R^C1 is hydrogen. 15. In embodiment 15, the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is heterocyclylalkyl, bicyclic heterocyclyl, or bicyclic heterocylalkylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl are substituted with R^d, R^e, R^f, and R^fl as defined therein.

16. In embodiment 16, the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is heterocyclylalkyl or bicyclic heterocylalkylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl of bicyclic heterocyclylalkyl are substituted with R^d, R^e, R^f, and R^fl as defined therein and alkyl of heterocyclylalkyl and bicyclic heterocyclylalkyl are substituted with one or two deuterium.

17. In embodiment 17, the compound of any one of embodiments 1 to 7, 15, and 16, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is heterocyclylalkyl where heterocyclyl of heterocyclylalkyl of R⁶ is substituted with R^d, R^e, R^f, and R^fl as defined therein (for avoidance of doubt, embodiment 17 covers heterocyclylalkyl where the alkyl of heterocyclylalkyl is substituted with one or two deuterium and is not substituted with one or two deuterium).

18. In embodiment 18, the compound of any one of embodiments 1 to 7, 15, and 17, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl of R⁶ is pyrrolidin-2-ylmethyl, piperidin-2-ylmethyl, or piperi din-3 -ylmethyl, preferably pyrrolidin-2-ylmethyl substituted with R^d, R^e, R^f, and R^fl as defined therein.

19. In embodiment 19, the compound of any one of embodiments 1 to 7, 15, 17, and 18, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl of R⁶ is pyrrolidin-2-ylmethyl of structure

substituted with R^e, R^f, and R^fl where Rⁿ is hydrogen.

20. In embodiment 20, the compound of any one of embodiments 1 to 7, 16, and 17, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl of R⁶ is pyrrolidin-2-ylmethyl-d2, piperidin-2-ylmethyl-d2, or piperi din-3 -ylmethyl-d2, preferably pyrrolidin-2-ylmethyl-d2 substituted with R^d, R^e, R^f, and R^fl as defined therein. 21. In embodiment 21, the compound of any one of embodiments 1 to 7, 15, and 16, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is bicyclic heterocycl alkyl alkyl substituted with R^d, R^e, R^f, and R^fl as defined therein (for avoidance of doubt, embodiment 21 covers bicyclic heterocyclylalkyl where the alkyl of bicyclic heterocy cl yl alkyl is substituted with one or two deuterium and is not substituted with one or two deuterium).

22. In embodiment 22, the compound of any one of embodiments 1 to 7, 15, and 21, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R⁶ is hexahydro- lH-pyrrolizin-7a-ylalkyl, preferably, hexahydro- 1H- pyrrolizin-7a-ylmethyl, where hexahydro- lH-pyrrolizin-7a-yl is substituted with R^d, R^e, R^f, and R^fl as defined therein.

23. In embodiment 19, the compound of any one of embodiments 1 to 7, 16, and 21, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R⁶ is hexahydro- lH-pyrrolizin-7a-ylalkyl-d2, preferably, hexahydro- lH-pyrrolizin-7a-ylmethyl-d2, where hexahydro- lH-pyrrolizin-7a-yl is substituted with R^d, R^e, R^f, and R^fl as defined therein.

24. In embodiment 24, the compound of any one of embodiments 1 to 7, 15, 21, and 22, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl is a ring of formula:

25. In embodiment 25, the compound of any one of embodiments 1 to 7, 15,

21, 22, and 24, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocy cl yl alkyl of R⁶ is a ring of formula:

are as defined therein and R^fl is hydrogen.

26. In embodiment 26, the compound of any one of embodiments 1 to 7, 15, 21, 22, 24, and 25, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocy cl yl alkyl of R⁶ is a ring of formula:

are as defined therein.

27. In embodiment 27, the compound of any one of embodiments 1 to 7, 16, 21, and 23, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocy cl yl alkyl of R⁶ is a ring of formula:

28, the compound of any one of embodiments 1 to 7, 16,

21, 23, and 27, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocy cl yl alkyl of R⁶ is a ring of formula:

are as defined therein and R^fl is hydrogen. 29. In embodiment 29, the compound of embodiment 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, heterocyclyl fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, by itself or as part of heterocyclyl fused bicyclic heterocyclylalkyl, or tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl are independently substituted with R^g, R^h, R¹ and R¹¹ as defined therein.

30. In embodiment 30, the compound of embodiment 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, or tricyclic heterocyclylalkyl, wherein fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl of heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl of tricyclic heterocyclylalkyl are independently substituted with R^g, R^h, R¹, and R¹¹ as defined therein and alkyl of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl are substituted with one or two deuterium.

31. In embodiment 31, the compound of embodiment 1 to 7 or 29, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is fused bicyclic heterocyclyl substituted with R^g, R^h, R¹, and R¹¹ as defined therein.

32. In embodiment 32, the compound of embodiment 1 to 7, 29, or 31, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R⁶ is a ring of formula:

ring A is phenyl or 5- or 6-membered heteroaryl and the fused bicyclic heterocyclyl is additionally substituted with R^h and R¹ where R^g, R^h and R¹ are as defined as defined therein, preferably ring A is phenyl or 5- or 6-membered heteroaryl substituted with R^h and R¹ as defined therein. 33. In embodiment 33, the compound of embodiment 1 to 7, 29, or 31, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R⁶ is a ring of formula:

ring A is phenyl, pyrazolyl, pyridinyl, or pyrimidinyleach ring substituted with R^h and R¹ as defined therein.

34. In embodiment 34, the compound of any one of embodiments 1 to 7, 29, and 30, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is fused bicyclic heterocylalkylalkyl where fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl is substituted with R^g, R^h, and R¹ as defined therein.

35. In embodiment 35, the compound of embodiment 1 to 7, 29, or 34, or a pharmaceutically acceptable salt thereof, is wherein fused bicyclic heterocyclylalkyl of R⁶ is a ring of formula:

ring A is phenyl or 5- or 6-membered heteroaryl and the fused bicyclic heterocyclyl is additionally substituted with R^h and R¹ where R^s, R^h and R¹ are as defined as defined therein.

36. In embodiment 36, the compound of embodiment 1 to 7, 29, 34, or 35, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R⁶ is a ring of formula:

ring A is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, each ring substituted with R^h and R¹ as defined therein.

37. In embodiment 37, the compound of embodiment 1 to 7, 30, or 34, or a pharmaceutically acceptable salt thereof, is wherein fused bicyclic heterocyclylalkyl of R⁶ is a ring of formula:

38. In embodiment 38, the compound of embodiment 1 to 7, 30, 34, or 37, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R⁶ is a ring of formula:

39. In embodiment 39, the compound of embodiment 1 to 7 and 29 to 38, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl and the fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl of R⁶ is 2,3-dihydro-lH- pyrrolo[2,l-a]isoindol-9b(5H)-yl, 2,3-dihydro-lH-pyrrolo[l,2-a]indol-9a(9H)-yl, l,3b,4,5,6,8-hexahydropyrrolo[3,2-a]pyrrolizin-3b-yl, l-methyl-l,3b,4,5,6,8- hexahydropyrrolo[4,3-a]pyrrolizin-3b-yl, 4b,6,7,9-tetrahydro-5H-pyrido[3,2-a]-pyrrolizin- 4b-yl, 3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-cd]isoindol-5-yl, or 1,2,3,5,10,10a- hexahydropyrrolo[l,2-b]isoquinolin-10a-yl, each ring substituted with R^g, R^h, and R¹ as defined therein.

40. In embodiment 40, the compound of any one of embodiments 1 to 7 and 29, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is tricyclic heterocyclyl substituted with R^g, R^h, and R¹ as defined therein.

41. In embodiment 41, the compound of any one of embodiments 1 to 7 and

29, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is tricyclic heterocyclylalkyl where tricyclic heterocyclyl of tricyclic heterocyclylalkyl is substituted with R^g, R^h, and R¹ as defined therein.

42. In embodiment 42, the compound of any one of embodiments 1 to 7 and

30, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is tricyclic heterocy cl yl alkyl where tricyclic heterocyclyl of tricyclic heterocyclylalkyl is substituted with R^g, R^h, and R¹ as defined therein and the alkyl of tricyclic heterocyclylalkyl is substituted with one or two deuterium.

43. In embodiment 43, the compound of any one of embodiments 1 to 7, 15, 21, 22, and 24, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R⁶ is a ring of formula:

44. In embodiment 44, the compound of any one of embodiments 1 to 7 and 15 to 43, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^sare independently alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, or alkoxyalkylidenyl.

45. In embodiment 45, the compound of any one of embodiments 1 to 7 and 15 to 44, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^s are alkylidenyl.

46. In embodiment 46, the compound of any one of embodiments 1 to 7 and 15 to 45, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^s are methylidenyl.

47. In embodiment 47, the compound of any one of embodiments 1 to 7 and 15 to 44, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^sare haloalkylidenyl.

48. In embodiment 48, the compound of any one of embodiments 1 to 7, 13, 15 to 44 and 47, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d, and R^s are independently =CHF, =CF₂, =C(H)CH₂F, =C(CH₃)F, or =C(H)CHF₂.

49. In embodiment 49, the compound of any one of embodiments 1 to 9, and 14 to 44, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d, and R^s are alkoxyalkylidenyl.

50. In embodiment 50, the compound of any one of embodiments 1 to 9, 14 to 44 and 49, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^sare independently =C(H)(CH₂)₂OCH₃ or =C(H)(CH₂)₂OC₂H₅. 51. In embodiment 51, the compound of any one of embodiments 1 to 7 and 15 to 44, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^s are deuterioalkylidenyl.

52. In embodiment 52, the compound of any one of embodiments 1 to 7 and 15 to 44, and 51, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^sare independently =CD2.

53. In embodiment 53, the compound of any one of embodiments 1 to 9 and 14 to 43, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d, and R^s are =CR⁷R⁸, =CR⁹R¹⁰, and =CR^UR¹², respectively.

54. In embodiment 54, the compound of any one of embodiments 1 to 9, 14 to 43, and 53, or a pharmaceutically acceptable salt thereof, is wherein R⁷, R⁹, and R¹¹ are hydrogen.

55. In embodiment 55, the compound of any one of embodiments 1 to 9, 14 to 43, and 53, or a pharmaceutically acceptable salt thereof, is wherein R⁷, R⁹, and R¹¹ are fluoro.

56. In embodiment 56, the compound of any one of embodiments 1 to 9, 14 to 43, and 53, or a pharmaceutically acceptable salt thereof, is wherein R⁷, R⁹, and R¹¹ are alkyl.

57. In embodiment 57, the compound of any one of embodiments 1 to 9, 14 to 43, 53, and 56, or a pharmaceutically acceptable salt thereof, is wherein R⁷, R⁹, and R¹¹ are independently methyl, ethyl, or propyl.

58. In embodiment 58, the compound of any one of embodiments 1 to 9, 14 to 43, and 53 to 57, or a pharmaceutically acceptable salt thereof, is wherein R⁸, R¹⁰, and R¹² are independently cyano, cycloalkyl, or cycloalkylalkyl.

59. In embodiment 59, the compound of any one of embodiments 1 to 9, 14 to 43, and 53 to 58, or a pharmaceutically acceptable salt thereof, is wherein R⁸, R¹⁰, and R¹² are independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutyl ethyl, or cyclopentyl ethyl.

60. In embodiment 60, the compound of any one of embodiments 1 to 9, 14 to 43, and 53 to 59, or a pharmaceutically acceptable salt thereof, is wherein R⁸, R¹⁰, and R¹² are cyano. 61. In embodiment 61, the compound of any one of embodiments 1 to 9, 14 to 43, and 53 to 57, or a pharmaceutically acceptable salt thereof, is wherein R⁸, R¹⁰, and R¹² are independently heterocyclyl, phenyl, or heteroaryl.

62. In embodiment 62, the compound of any one of embodiments 1 to 9, 14 to 43, 53 to 57, and 61, or a pharmaceutically acceptable salt thereof, is wherein R⁸, R¹⁰, and R¹² are independently phenyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, or 5- or 6-membereing heteroaryl.

63. In embodiment 63, the compound of any one of embodiments 1 to 9 and 14 to 43, and 53, or a pharmaceutically acceptable salt thereof, is wherein R⁷ and R⁸, R⁹ and R¹⁰, and R¹¹ and R¹² together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy.

64. In embodiment 64, the compound of any one of embodiments 1 to 9, 14 to 43, 53, and 63, or a pharmaceutically acceptable salt thereof, is wherein R⁷ and R⁸, R⁹ and R¹⁰, and R¹¹ and R¹² together with the carbon atom to which they are attached form cyclopropyl, cyclobutylene, or cyclopentylene, each ring optionally substituted with methyl, fluoro, or methoxy.

65. In embodiment 65, the compound of any one of embodiments 1 to 9, 15 to 43, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^sare independently hydrogen, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy.

66. In embodiment 66, the compound of any one of embodiments 1 to 9, 15 to 43 and 65, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^sare independently hydrogen or fluoro.

67. In embodiment 67, the compound of any one of embodiments 1 to 9, 15 to 43 and 65, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^sare independently hydrogen or halo.

68. In embodiment 68, the compound of any one of embodiments 1 to 9, 15 to 43 and 65, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^sare independently haloalkyl or haloalkoxy.

69. In embodiment 69, the compound of any one of embodiments 1 to 9, 15 to 43 and 65, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^sare independently alkyl or alkoxy. 70. In embodiment 70, the compound of any one of embodiments 1 to 69, or a pharmaceutically acceptable salt thereof, is wherein R^b, R^e, and R^h are independently - (Q^ni-OQC NR^R¹⁴.

71. In embodiment 71, the compound of any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof, is wherein Q¹ is alkylene.

72. In embodiment 72, the compound of any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof, is wherein Q¹ is deuterioalkylene.

73. In embodiment 73, the compound of any one of embodiments 1 to 72, or a pharmaceutically acceptable salt thereof, is wherein Q¹ is methylene, ethylene, -CH(CH₃)- , -C(CH₃)₂-, or -CD₂-.

74. In embodiment 74, the compound of any one of embodiments 1 to 71, and 73, or a pharmaceutically acceptable salt thereof, is wherein Q¹ is methylene, ethylene, - CH(CH₃)-, -C(CH₃)₂, preferably methylene.

75. In embodiment 75, the compound of any one of embodiments 1 to 70, 72, and 73, or a pharmaceutically acceptable salt thereof, is wherein Q¹ is -CD₂-.

76. In embodiment 76, the compound of any one of embodiments 1 to 75, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R¹⁴ is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl substituted with R^j and R^k.

77. In embodiment 77, the compound of any one of embodiments 1 to 76, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is hydrogen or deuterium.

78. In embodiment 78, the compound of any one of embodiments 1 to 76, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is alkyl.

79. In embodiment 79, the compound of any one of embodiments 1 to to 76, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is haloalkyl.

80. In embodiment 80, the compound of any one of embodiments 1 to 76, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is haloalkoxyalkyl.

81. In embodiment 81, the compound of any one of embodiments 1 to 76, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is alkoxyalkyl.

82. In embodiment 82, the compound of any one of embodiments 1 to 76, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is deuterioalkyl. 83. In embodiment 83, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is alkoxy.

84. In embodiment 84, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is alkoxyalkyl.

85. In embodiment 85, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is haloalkyl.

86. In embodiment 86, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is haloalkoxyalkyl.

87. In embodiment 87, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is cycloalkyl.

88. In embodiment 88, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is deuterioalkyl.

89. In embodiment 89, the compound of any one of embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, is wherein R¹⁴ is heterocyclyl substituted with R^j and R^k.

90. In embodiment 90, the compound of any one of embodiments 1 to 89, or a pharmaceutically acceptable salt thereof, is wherein R¹³ is hydrogen, methyl, methyl-d3, methoxyethyl, ethoxyethyl, or propoxyethyl; and R¹⁴ is methyl-d3, cyclopropyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethoxymethyl, 2,2,2-trifluoroethoxymethyl, methoxy ethyl, ethoxy ethyl, ox etan-3 -yl, tetrahydrofuranyl, or tetrahydropyranyl.

91. In embodiment 91, the compound of any one of embodiments 1 to 75, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted with R^m, Rⁿ, R°, and R^p and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R^q, R^r, and R^s.

92. In embodiment 92, the compound of any one of embodiments 1 to 75, and 91, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl substituted with R^m, Rⁿ, R°, and R^p. 93. In embodiment 93, the compound of any one of embodiments 1 to 75, and

91, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, each ring independently substituted with R^q, R^r, and R^s.

94. In embodiment 94, the compound of any one of embodiments 1 to 75, 91, and 92, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl selected from azetidin-1- yl, pyrrolidin-l-yl, piperidin-l-yl, piperazin- 1-yl, morpholin-l-yl, and homomorpholin-1- yl, each ring substituted with R^m, Rⁿ, R°, and R^p.

95. In embodiment 95, the compound of any one of embodiments 1 to 75, 91,

92, and 94 , or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl selected from azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, piperazin- 1-yl, morpholin-l-yl, and homomorpholin-l-yl, each ring substituted with R^m, Rⁿ, R°, and R^p where R^m and Rⁿ are independently selected from hydrogen, deuterium, methyl, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, or methoxy, R° is hydrogen, deuterium, methoxymethyl, or fluoro, and R^p is hydrogen, deuterium, or fluoro.

96. In embodiment 96, the compound of any one of embodiments 1 to 75, 91, 92, 94, and 95, or a pharmaceutically acceptable salt thereof, is wherein R^m, Rⁿ, R°, and R^p are hydrogen.

97. In embodiment 97, the compound of any one of embodiments 1 to 75, 91, 92, 94, and 95, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl selected from 3-methoxymethylazetidin-l-yl, 2-methoxymethyl-piperidin-l-yl, 3, 3,4,4- tetrafluoropyrrolidin-l-yl, morpholin-l-yl. 2,6-dimethylmorpholin-4-yl, 2,2- dimethylmorpholin-4-yl, 2-(trifluoromethyl)morpholin-4-yl, 2,2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, and 2-(difluorom ethyl )morpholin-4-yl.

98. In embodiment 98, the compound of any one of embodiments 1 to 75, 91, 92, and 94 to 97, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form heterocyclyl selected from morpholin-l-yl. 2,6-dimethylmorpholin-4-yl, 2,2-dimethylmorpholin-4-yl, 2- (trifluoromethyl)morpholin-4-yl, 2,2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3- methylmorpholin-4-yl, and 2-(difluorom ethyl )morpholin-4-yl.

99. In embodiment 99, the compound of any one of embodiments 1 to 75, 91, and 93, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl substituted with R^q, R^r, and R^s.

100. In embodiment 100, the compound of any one of embodiments 1 to 75, 91, and 93, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form bridged heterocyclyl substituted with R^q, R^r, and R^s.

101. In embodiment 101, the compound of any one of embodiments 1 to 75, 91, and 93, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form fused heterocyclyl substituted with R^q, R^r, and R^s.

102. In embodiment 102, the compound of any one of embodiments 1 to 75, 91, and 93, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form spiroheterocyclyl substituted with R^q, R^r, and R^s.

103. In embodiment 103, the compound of any one of embodiments 1 to 75, 91, and 99 to 102, or a pharmaceutically acceptable salt thereof, is wherein R¹³ and R¹⁴ together with the nitrogen atom to which they are attached form a ring selected from:

each ring substituted with R^q, R^r, and R^s.

104. In embodiment 104, the compound of any one of embodiments 1 to 75, 91, and 99 to 103, or a pharmaceutically acceptable salt thereof, is wherein R^s is hydrogen.

105. In embodiment 105, the compound of any one of embodiments 1 to 75, 91, and 99 to 103, or a pharmaceutically acceptable salt thereof, is wherein R^rand R^s are hydrogen.

106. In embodiment 106, the compound of any one of embodiments 1 to 75, 91, and 99 to 105, or a pharmaceutically acceptable salt thereof, is wherein R^q, R^r, and R^s (where applicable) are independently selected from hydrogen, methyl, methoxy, or fluoro.

107. In embodiment 107, the compound of any one of embodiments 1 to 69, or a pharmaceutically acceptable salt thereof, is wherein R^b, R^e, and R^h are independently - (Q²)-OR^13a.

108. In embodiment 108, the compound of any one of embodiments 1 to 69 and 107, or a pharmaceutically acceptable salt thereof, is wherein Q² is alkylene.

109. In embodiment 109, the compound of any one of embodiments 1 to 69, 107, and 108, or a pharmaceutically acceptable salt thereof, is wherein Q² is deuterioalkylene.

110. In embodiment 110, the compound of any one of embodiments 1 to 69 and 107 to 109, or a pharmaceutically acceptable salt thereof, is wherein Q² is methylene, methylene-d2, ethylene, propylene, or butylene.

111. In embodiment 111, the compound of any one of embodiments 1 to 69 and 107 to 110, or a pharmaceutically acceptable salt thereof, is wherein Q² is methylene, methylene-d2, ethylene, or propylene.

112. In embodiment 112, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) substituted with R R^u, and R^v independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

113. In embodiment 113, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is cycloalkylalkyl (such as cyclopropylmethyl or -ethyl, cyclobutylmethyl or -ethyl, cyclopentylmethyl or -ethyl or cyclohexylmethyl or -ethyl) is substituted with R R^u, and R^v independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

114. In embodiment 114, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is haloalkoxyalkyl such as trifluoromethoxymethyl or difluoromethoxymethyl.

115. In embodiment 115, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is heterocyclyl (such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl) substituted with R R^u, and R^v.

116. In embodiment 116, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is heterocyclyl alkyl (such as pyrrolidinylmethyl or -ethyl, piperidinylmethyl or -ethyl, piperazinylmethyl or -ethyl or morpholinylmethyl or -ethyl) substituted with R R^u, and R^v.

117. In embodiment 117, the compound of any one of embodiments 1 to 66 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is phenyl substituted with R R^u, and R^v.

118. In embodiment 118, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is phenylmethyl or ethyl substituted with R R^u, and R^v.

119. In embodiment 119, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is heteroaryl (such as furanyl, pyridyl, pyrazinyl, quinolinyl, or isoquinolinyl) substituted with R R^u, and R^v.

120. In embodiment 120, the compound of any one of embodiments 1 to 69 and 107 to 111, or a pharmaceutically acceptable salt thereof, is wherein R^13a is heteroaryalkyl (such as furanylmethyl or -ethyl, pyridylmethyl or -ethyl, pyrazinylmethyl or -ethyl, quinolinylmethyl or -ethyl, or isoquinolinylmethyl or -ethyl) substituted with R R^u, and R^v.

121. In embodiment 121, the compound of any one of embodiments 1 to 120, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and R¹ are independently hydrogen, deuterium, methyl, ethyl, methoxy, ethoxy, methyloxy, ethyloxy, chloro, or fluoro.

122. In embodiment 122, the compound of any one of embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and R¹ are hydrogen.

123. In embodiment 123, the compound of any one of embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and R¹ are deuterium.

124. In embodiment 124, the compound of any one of embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and R¹ are independently methyl, methoxy, methyloxy, chloro, or fluoro.

125. In embodiment 125, the compound of any one of embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and R¹ are independently chloro or fluoro, preferably, R^c, R^f, and R¹ are fluoro.

126. In embodiment 126, the compound of any one of embodiments 1 to 125, or a pharmaceutically acceptable salt thereof, is wherein R^cl, R^fl, and R¹¹ are independently selected from hydrogen, deuterium, or fluoro.

127. In embodiment 127, the compound of any one of embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, is wherein R^cl, R^fl, and R¹¹ are hydrogen.

128. In embodiment 128, the compound of any one of embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, is wherein R^cl, R^fl, and R¹¹ are deuterium.

129. In embodiment 129, the compound of any one of embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, is wherein R^cl, R^fl, and R¹¹ are fluoro.

130. In embodiment 130, the compound of any one of embodiments 1 to 129, or a pharmaceutically acceptable salt thereof, is wherein Y of -Y-R⁶ is O.

131. In embodiment 130, the compound of any one of embodiments 1, 2, and 8 to 130, or a pharmaceutically acceptable salt thereof, is wherein q is 0.

132. In embodiment 132, the compound of any one of embodiments 1, 2 and 8 to 130, or a pharmaceutically acceptable salt thereof, is wherein q is 1.

133. In embodiment 133, the compound of any one of embodiments 1, 2 and 8 to 130, or a pharmaceutically acceptable salt thereof, is wherein q is 2.

134. In embodiment 134, the compound of any one of embodiments 1, 2, 4, 6, and 8 to 133, or a pharmaceutically acceptable salt thereof, is wherein p is 1. 135. In embodiment 135, the compound of any one of embodiments 1, 2, 4, 6, and 8 to 133, or a pharmaceutically acceptable salt thereof, is wherein p is 2.

136. In embodiment 136, the compound of any one of embodiments 1, 2, 6 and 8 to 133, or a pharmaceutically acceptable salt thereof, is wherein p is 3.

137. In embodiment 137, the compound of any one of embodiments Ito 133, or a pharmaceutically acceptable salt thereof, is wherein X is N.

138. In embodiment 138, the compound of any one of embodiments 1 to 136, or a pharmaceutically acceptable salt thereof, is wherein X is CH (or C when attached to any one of R¹ and R²).

138a. In embodiment 138a, the compound of embodiment 138, or a pharmaceutically acceptable salt thereof, is wherein R¹ is halo.

139. In embodiment 139, the compound of any one of embodiments 1 to 138a, or a pharmaceutically acceptable salt thereof, is wherein R^la is hydrogen.

140. In embodiment 140, the compound of any one of embodiments 1 to 138a, or a pharmaceutically acceptable salt thereof, is wherein R^lais alkyl, preferably methyl or ethyl.

141. In embodiment 141, the compound of any one of embodiments 1 to 138a, or a pharmaceutically acceptable salt thereof, is wherein R^la is alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, cyanomethyl, or cyanoethyl.

142. In embodiment 142, the compound of any one of embodiments 1 to 138a, or a pharmaceutically acceptable salt thereof, is wherein R^la is alkylidenyl, preferably methylidene.

143. In embodiment 143, the compound of any one of embodiments 1 to 142, or a pharmaceutically acceptable salt thereof, is wherein R^la is alkoxy, halo, haloalkyl, or hydroxy.

144. In embodiment 144, the compound of any one of embodiments 1 to 142, or a pharmaceutically acceptable salt thereof, is wherein R^la is cyanomethyl, or cyanoethyl.

145. In embodiment 145, the compound of any one of embodiments 1 to 142, or a pharmaceutically acceptable salt thereof, is wherein R^la is cyanomethyl attached to carbon adjacent to >N-L-R⁵. 146. In embodiment 146, the compound of any one of embodiments 1 to 145, or a pharmaceutically acceptable salt thereof, is wherein R^lb, R^lc, and R^ld are independently selected from hydrogen, halo, and alkyl.

147. In embodiment 147, the compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof, is wherein R^lb, R^lc, and R^ld are independently selected from hydrogen.

148. In embodiment 148, the compound of any one of embodiments 1 to 145 and 147, or a pharmaceutically acceptable salt thereof, is wherein R^lb, R^lc, and R^ld are independently selected from hydrogen, fluoro, and methyl.

149. In embodiment 149, the compound of any one of embodiments 1 and 8 to 148 or a pharmaceutically acceptable salt thereof, is wherein R^la and R^lb are attached to the same carbon of the ring and combine to form cycloalkylene optionally substituted with alkyl, halo, alkoxy, cyano, or hydroxy and R^lc is hydrogen.

150. In embodiment 150, the compound of any one of embodiments 1 to 145 and 149 or a pharmaceutically acceptable salt thereof, is wherein R^la and R^lb are attached to the same carbon of the ring and combine to form cyclopropylene or cyclopentylene.

151. In embodiment 151, the compound of any one of embodiments 1 to 150, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, heteroaryl, or fused heteroaryl, wherein aryl, heteroaryl, and fused heteroaryl are substituted with R³³, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^ddis hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkylthio, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

152. In embodiment 152, the compound of any one of embodiments 1 to 150, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is alkylene and R¹⁵ is cycloalkyl, aryl, or fused heteroaryl, wherein aryl, fused heteroaryl, and heteroaryl are substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkynyl, or halo, and R^ddis hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

153. In embodiment 153, the compound of any one of embodiments 1 to 150, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is -C(O)- and R¹⁵ is cycloalkyl, aryl, fused heteroaryl, or heteroaryl, wherein aryl, fused heteroaryl and heteroaryl are substituted with R³³, R^bb, R^cc and R^dd wherein R³³ and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkynyl, or halo, and R^ddis hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

154. In embodiment 154, the compound of any one of embodiments 1 to 150, or a pharmaceutically acceptable salt thereof, is wherein R¹⁵ is cycloalkyl, fused cycloalkyl, aryl, or heteroaryl wherein aryl, and heteroaryl are substituted with R³³, R^bb, R^cc and R^dd wherein R³³ and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^ddis hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

155. In embodiment 155, the compound of any one of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is phenyl or naphthyl substituted with R³³, R^bb, R^cc and R^dd.

156. In embodiment 156, the compound of any one of embodiments 1 to 151 and 156, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is phenyl or naphthyl substituted with R³³, R^bb, R^cc and R^dd where R³³ and R^bb are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl, R^cc is hydrogen, fluoro, alkynyl, and R^ddis hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl. 157. In embodiment 157, the compound of any one of embodiments 1 to 156, or a pharmaceutically acceptable salt thereof, is wherein R^aa and R^bb independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R^cc is hydrogen, ethynyl, 2-cyanovinyl, 2-cyanoethyn-l-yl, or fluoro, and R^ddis hydrogen, methyl, fluoro, amino, or cyclopropyl.

158. In embodiment 158, the compound of any one of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is heteroaryl or fused heteroaryl substituted with R^aa, R^bb, R^cc and R^dd.

159. In embodiment 159, the compound of any one of embodiments 1 to 151 and 158, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, benzothiazolyl) substituted with R^aa, R^bb, R^cc and R^dd.

160. In embodiment 160, the compound of any one of embodiments 1 to 151 and 158, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is bicyclic heteroaryl (e,g, quinolinyl, isoquinolinyl, or indazolyl), substituted with R^aa, R^bb, R^cc and R^dd.

161. In embodiment 161, the compound of any one of embodiments 1 to 151 and 158 to 160, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl is substituted with R^aa, R^bb, and R^dd where R^aa and R^bb independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R^ddis hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl.

162. In embodiment 162, the compound of any one of embodiments 1 to 151 and 158 to 161, or a pharmaceutically acceptable salt thereof, is wherein R^aa and R^bb are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R^cc is hydrogen or fluoro, and R^ddis hydrogen, methyl, fluoro, amino, or cyclopropyl. 163. In embodiment 163, the compound of any one of embodiments 1 to 162, or a pharmaceutically acceptable salt thereof, is wherein R^aa, R^bb, and R^dd are independently hydrogen or halo, and R^cc is alkynyl.

164. In embodiment 164, the compound of any one of embodiments 1 to 162, or a pharmaceutically acceptable salt thereof, is wherein wherein R^cc is hydrogen and R^aa,

R^bb, and R^dd are independently hydrogen, alkyl, haloalkyl or amino.

165. In embodiment 165, the compound of any one of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is:

substituted with R^aa, R^bb, and R^dd, wherein R^aa, R^bb, and R^dd are independently hydrogen or halo, and R^ccis alkynyl.

166. In embodiment 166, the compound of any one of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is pyridyl substituted with R^aa, R^bb, R^cc and R^dd, wherein R^cc is hydrogen and R^aa, R^bb, and R^dd are independently hydrogen, alkyl, haloalkyl or amino.

167. In embodiment 167, the compound of any one of embodiments 1 to 151 and 155 to 157, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is:

168. In embodiment 168, the compound of any one of embodiments 1 to 151,

155 to 157, and 167, or a pharmaceutically acceptable salt thereof, is wherein R⁴is -Q-R¹⁵

5 where Q is bond and R¹⁵ is:

169. In embodiment 169, the compound of any one of embodiments 1 to 151, 155 to 157, 167, and 168, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is - Q-R¹⁵ where Q is bond and R¹⁵ is:

170. In embodiment 170, the compound of any one of embodiments 1 to 151 and 158-161, or a pharmaceutically acceptable salt thereof, is wherein R⁴ is -Q-R¹⁵ where Q is bond and R¹⁵ is:

171. In embodiment 171, the compound of any one of embodiments 1 to 170, or a pharmaceutically acceptable salt thereof, is wherein R¹ is hydrogen, halo, or alkyl, and R² is hydrogen, halo, cycloalkyl, cycloalkyloxy, or alkyl.

172. In embodiment 172, the compound of any one of embodiments 1 to 171, or a pharmaceutically acceptable salt thereof, is wherein R¹ and R² are each hydrogen.

173. In embodiment 173, the compound of any one of embodiments 1 to 171, or a pharmaceutically acceptable salt thereof, is wherein R¹ is hydrogen or chloro and R² is hydrogen, fluoro, cyclopropyl, or cyclopropyl oxy.

174. In embodiment 174, the compound of any one of embodiments 1 to 171 or a pharmaceutically acceptable salt thereof, is wherein R¹ is hydrogen and R² is fluoro or cyclopropyl.

175. In embodiment 175, the compound of any one of embodiments 1 to 171, 173, and 174, or a pharmaceutically acceptable salt thereof, is wherein R¹ is hydrogen and R² is fluoro or cyclopropyl and R² is attached to carbon meta to X.

176. In embodiment 176, the compound of any one of embodiments 1 to 171, 173, and 174, or a pharmaceutically acceptable salt thereof, is wherein R¹ is hydrogen or chloro and R² is fluoro and R² is attached to carbon meta to X.

177. In embodiment 177, the compound of any one of embodiments 1 to 176, or a pharmaceutically acceptable salt thereof, is wherein L is bond, alkylene, or cycloalkylene where alkylene and cycloalkylene are substituted with R¹⁶. 178. In embodiment 177, the compound of any one of embodiments 1 to 177, or a pharmaceutically acceptable salt thereof, is wherein L is bond.

179. In embodiment 177, the compound of any one of embodiments 1 to 177, or a pharmaceutically acceptable salt thereof, is wherein L is alkylene substituted with R¹⁶.

180. In embodiment 180, the compound of any one of embodiments 1 to 177 and 179, or a pharmaceutically acceptable salt thereof, is wherein the alkylene of L is selected from methylene or ethylene substituted with R¹⁶.

181. In embodiment 181, the compound of any one of embodiments 1 to 177 and 179, or a pharmaceutically acceptable salt thereof, is wherein the alkylene of L is selected from methylene, ethylene, -CHR¹⁶- or -CHR¹⁶-CH2- where each R¹⁶ is other than hydrogen.

181a. In embodiment 181a, the compound of any one of embodiments 1 to 177 and 179, or a pharmaceutically acceptable salt thereof, is wherein the alkylene of L is selected from methylene, ethylene, -CHR¹⁶- or -CHR¹⁶-CH2- where each R¹⁶ is alkyl.

181a. In embodiment 181a, the compound of any one of embodiments 1 to 177 and 179, or a pharmaceutically acceptable salt thereof, is wherein the alkylene of L is selected from methylene, ethylene, -CHR¹⁶- or -CHR¹⁶-CH2- where each R¹⁶ is methyl or ethyl.

182. In embodiment 182, the compound of any one of embodiments 1 to 177 and 179, or a pharmaceutically acceptable salt thereof, is wherein the alkylene of L is selected from methylene, ethylene, -CHR¹⁶- or -CHR¹⁶-CH2- where each R¹⁶ is alkyl, dialkylamino, or cycloalkyl.

183. In embodiment 183, the compound of any one of embodiments 1 to 177 and 179 to 182, or a pharmaceutically acceptable salt thereof, is wherein the alkylene of L is selected from methylene, ethylene, -CHR¹⁶- or -CHR¹⁶-CH2- where each R¹⁶ is methyl or cyclopropyl.

184. In embodiment 184, the compound of any one of embodiments 1 to 183, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is fused cycloalkyl or heteroaryl, each ring substituted with R¹⁷, R¹⁸, and R¹⁹.

185. In embodiment 185, the compound of any one of embodiments 1 to 184, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is fused cycloalkyl substituted with R¹⁷, R¹⁸, and R¹⁹. 186. In embodiment 186, the compound of any one of embodiments 1 to 184, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is heteroaryl substituted with R¹⁷, R¹⁸, and R¹⁹.

186a. In embodiment 186a, the compound of any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof, is wherein R¹⁷, R¹⁸, and R¹⁹ are selected from hydrogen and NR^kkR^mm, wherein R^kk and R^mm are each selected from hydrogen and alkyl.

186b. In embodiment 186b, the compound of any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof, is wherein R¹⁷, R¹⁸, and R¹⁹ are selected from hydrogen and NR^kkR^mm, wherein R^kk and R^mm are each hydrogen.

187. In embodiment 187, the compound of any one of embodiments 1 to 184 and 186b, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is 5 or 6 membered heteroaryl (such as imidazolyl, thiazoly, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl) substituted with R¹⁷, R¹⁸, and R¹⁹.

188. In embodiment 188, the compound of any one of embodiments 1 to 187, or a pharmaceutically acceptable salt thereof, is wherein -L-R⁵ is selected from:

189. In embodiment 188, the compound of any one of embodiments 1 to 188, or a pharmaceutically acceptable salt thereof, is wherein -L-R⁵ is selected from:

GENERAL SYNTHESIS

Compounds Formula (I) can be made by the methods depicted in the reaction schemes shown below.

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds Formula (I) can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.

Compounds of Formula (I) can be prepared by methods known in the art. For example, compound of Formula (I) where R³ is -O-R⁶, Z¹ is O or S, q is 0 and other groups are as defined in the Summary can be prepared as illustrated and described in

Treatment of a compound of formula 1-a where X¹, X², and X³ are halo, with an amine of formula 1-e where Z¹ is OH or SH and other groups are as defined in summary provides a compound of formula 1-b. Compound 1-b can undergo cyclization in the presence of a suitable coupling reagent such as BOP-CI to provide compound of formula 1-c. Coupling reaction between compound 1-c and a suitable organometallic reagent of formula R⁴-M where R⁴ is cycloalkyl, aryl or heteroaryl as defined in the Summary or a precursor group thereof and M is boronic acid, boronic ester, or stannane, under Suzuki, Negeshi, and Stille reaction conditions respectively, to provide a compound of formula 1- d. Displacement of X² group in compound 1-d with an alcohol of formula 1-f provides a compound of formula I. Amine of formula 1-a, alcohols of formula 1-e and 1-f are either commercially available or can be made by methods known in the art.

For example, compound of formula 1-a where X¹, X are halogen, X is Cl, and other groups are as defined in Summary can be prepared as illustrated and described below.

1-a

Compounds of formula 2-a where X¹, X³ are halogen, and R¹ and R² are as defined in Summary' can be converted to amide 2-b under standard amide coupling conditions such as HATU, NH4CI and DIPEA. Compound 2-b can undergo cyclization to provide compound of formula 1-a by treating with thiophosgene.

Representative methods for preparing compound of formula 1-f are described in in the Synthetic Examples below.

Compound of Formula (I) where R³ is -O-R⁶, Z¹ is CH2, q is 1 and other groups are as defined in the Summary can be prepared as illustrated and described in Scheme 2.

Scheme 2

Hydroboration of compound 1-g, followed by coupling the resulting product with compound 1-a under standard Suzuki coupling condition can provide compound of formula 1-i. Compound 1-i can be converted to compound (I) as described in Scheme 1. Compounds of Formula (I) where R^b is -(Q¹)OC(O)NR¹³R¹⁴ where Q¹ is alkylene can be from a compound where R^b is a precusor group of -(Q¹)OC(O)NR¹³R¹⁴ as illustrated and described in Scheme 3 below.

Removal of the hydroxy protecting group in formula 3-a (synthesized as described in Scheme 1 or 2 above) provides a compound of formula 3-b. Treatment of a compound of formula 3-b with a coupling agent such as CDI, (4-nitrophenyl) carbonochloridate and the like, followed by treatment of the resulting intermediate with an amine of formula HNR¹³R¹⁴, where R¹³ and R¹⁴ are as defined in the Summary provides a compound of formula I.

Utility The present disclosure provides treatment of cancer mediated by K-ras, in particular with K-ras G12V mutants. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. In certain embodiments the lung cancer is a non- small cell lung carcinoma (NSCLC), for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

K-ras G12V mutations are observed in hematological malignancies that affect blood, bone marrow, and/or lymph nodes. As such the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and/ or other leukemias, lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma, plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom’s macroglubunemia.

The compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be used for the treatment of a hyperproliferative disorder or metastasis in human who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. The compounds of Formula(I), or a pharmaceutically acceptable salt thereof can also be used for the treatment of a non- cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).

Testing

The K-Ras G12V activity of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be tested using the in vitro assay described in Biological Examples 1 below.

Pharmaceutical Compositions

In general, the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound Formula (I), i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

In general, compounds Formula (I) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.

The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

The compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In addition to the formulations described previously, the compounds of Formula (I) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.

For administration by inhalation, compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

The level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.

Combinations and Combination Therapies

The compounds of Formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. When a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The combination therapy may also include therapies in which the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) and the other active ingredients may be used in lower doses than when each is used singly. The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

Where the subject in need is suffering from or at risk of suffering from cancer, the patient can be treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof in any combination with one or more other anti-cancer agents including but not limited to:

MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032, CAS No. 918504-65-1), Dabrafenib (CAS No. 1195765-45- 7), Encorafenib (LGX818 CAS No. 1269440-17-6), TQ-B3233, XL-518 (Cas No. 1029872- 29-4, available from ACC Corp); trametinib (CAS No. 871700-17-3), selumetinib (AZD6244 CAS No. 606143-52-6), TQ-B3234, PD184352 (CAS No. 212631- 79-3), PD325901 (CAS No. 391210-10-9), TAK-733 (CAS No. 1035555-63-5), pimasertinib (CAS No. 1236699-92-5), binimetinib (CAS No. 606143-89-9), refam etinib (CAS No. 923032-37-5), cobimetinib (GDC- 0973 CAS No. 934660-93-2), AZD8330 (CAS No. 869357-68-6), BVD-523 (CAS No. 869886-67-9), LTT462 (CAS No. 869886- 67-9), AMG510 (CAS No. 2296729-00-3), ARS853 (CAS No. 1629268-00-3), and any RAS inhibitors disclosed in patents WO2016049565, W02016164675,W02016168540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W02017058805,W02017058807, W02017058902, WO2017058915, W02017070256, WO2017087528, W02017100546, WO2017172979, W02017201161, W02018064510, WO20 18068017, and WO2018119183;

SHP2 inhibitors including but not limited to: SHP099 (CAS No. 2200214-93-1), TNO155 (CAS No. 1801765-04-7), RMC4630, JAB-3312, JAB-3068 and ERAS-601;

S0S1 inhibitors including but not limited to BI1701963 and BAY-293;

CSF1R inhibitors (PLX3397, LY3022855,) and CSF1R antibodies (IMC-054, RG7155);

TGF beta receptor kinase inhibitor such as LY2157299;

BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (CAS No. 152459- 95-5); Inilotinib hydrochloride; Nilotinib (CAS No. 923288-95-3); Dasatinib (BMS- 345825 CAS No. 302962-49-8); Bosutinib (SKI-606 CAS No. 380843-75-4); Ponatinib (AP24534 CAS No. 943319-70-8); Bafetinib (INNO406 CAS No. 859212-16-1); Danusertib (PHA-739358 CAS No. 827318-97-8), AT9283 (CAS No. 896466-04-9); Saracatinib (AZD0530 CAS No. 379231-04-6); and PF-03814735 (CAS 942487-16-3);

ALK inhibitors: PF-2341066 (XALKOPJ® ; crizotinib); 5-chloro-N4-(2- (isopropyl-sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-l-yl)piperidin-l- yl)phenyl)pyrimidine-2,4-diamine; GSK1838705A (CAS No. 1116235-97-2); CH5424802 (CAS No. 1256580-46-7); Ceritinib (ZYKADIA CAS No. 1032900-25-6); TQ-B3139, and TQ-B3101;

PI3K inhibitors: 4-[2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-piperazin-l- yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730), BEZ235 or NVP- BEZ235 (CAS No. 915019-65-7), disclosed in PCT Publication No. WO 06/122806);

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)- 2- pyridin-2- ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369), Brivanib Alaninate ((S)-((R)-l-(4- (4-fluoro-2-methyl-4H-indol- 5-yl oxy)-5-methylpyrrolo[2,l-f] [1,2, 4]triazin-6- yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3- dihydro-3,3- dimethyl- lH-indol-6-yl)-2-[(4- pyridinylmethyl)amino]-3- pyridinecarboxamide, and described in PCT Publication No. WO 02/066470), pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192), sorafenib (sold under the tradename Nexavar®, CAS No. 284461-73-0); or AL-2846;

MET inhibitor such as foretinib (CAS No. 849217-64-7), cabozantinib (CAS No. 1140909-48-3), capmatinib (CAS No. 1029712-80-8), tepotinib (CAS No. 1100598-32-0), savolitinib (CAS No. 1313725-88-0, or crizotinib (CAS No. 877399-52-5);

FLT3 inhibitors - sunitinib malate (CAS No. 341031-54-7, sold under the tradename Sutent® by Pfizer); PKC412 (CAS No. 120685-11-2, midostaurin); tandutinib (CAS No. 387867-13-2), sorafenib (CAS No. 284461-73-0), lestaurtinib (CAS No. : 111358-88-4), KW-2449 (CAS No. 1000669-72-6), quizartinib (AC220, CAS No. 950769-58-1), or crenolanib (CAS No. 670220-88-9);

Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3- furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), or panitumumab (sold under the tradename Vectibix® by Amgen);

HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(d imethylamino)but-2- enamide, and described PCT Publication No. WO 05/028443), lapatinib (CAS No. 231277-92-2) or lapatinib ditosylate (CAS No: 388082-77-7 ) (sold under the trademark Tykerb® by GlaxoSmithKline); or Trastuzumab emtansine (in the United States, ado- trastuzumab emtansine, trade name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1);

HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by Genentech);

FGFR inhibitors: Erdafitinib (CAS No. 1346242-81-6), Pemigatinib (CAS No. 1513857-77-6) or Infigratinib (CAS No. 872511-34-7)

Aurora kinase inhibitors: TAS-119 (CAS No. 1453099-83-6), LY3295668 (CAS No. 1919888-06-4), or alisertib (CAS No. 1028486-01-2);

CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), or ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);

Tyrosine kinase inhibitors: Erlotinib hydrochloride (CAS No. 183319-69-9, sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH- indazol-4-yl)phenyl]-N'-(2- fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (CAS No. 341031-54-7, sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5- methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin4-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No. 6,780,996), dasatinib (CAS No. 302962-49-8, sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (CAS No. 444731- 52-6, also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib (CAS No. 152459-95-5) and imatinib mesylate (CAS No. 220127-57-1) (sold under the tradenames Gilvec® and Gleevec® by Novartis);

DNA Synthesis inhibitors: Capecitabine (CAS No. 154361-50-9) (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (CAS No. 122111-03-9) (sold under the trademark Gemzar® by Eli Lilly and Company), or nelarabine ((2R3S,4R,5R)- 2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4- diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);

Antineoplastic agents: oxaliplatin (CAS No. 61825-94-3) (sold under the tradename Eloxatin® ay Sanofi- Aventis and described in US Patent No. 4,169,846);

Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen);

Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (CAS No. 191732-72-6, also known as CC-5013, sold under the tradename Revlimid®), or thalidomide (CAS No. 50- 35-1, sold under the tradename Thalomid®);

CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc);

Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech);

Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4- (m ethyl sulfony 1)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958);

Phospholipase A2 inhibitors: Anagrelide (CAS No. 58579-51-4, sold under the tradename Agrylin®);

BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]met hyl]- 1- piperazinyl]-N-[[4-[[(lR)-3-(4-morpholinyl)-l-[(phenylthio)m ethyl]propyl]amino]-3- [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386);

MCL-1 inhibitors: MIK665 (CAS No. 1799631-75-6, S64315), AMG 397, and AZD5991 (CAS No. 2143010-83-5); Aromatase inhibitors: Exemestane (CAS No. 107868-30-4, sold under the trademark Aromasin® by Pfizer), letrozole (CAS No. 112809-51-5, sold under the tradename Femara® by Novartis), or anastrozole (CAS No. 120511-73-1, sold under the tradename Arimidex®);

Topoisomerase I inhibitors: Irinotecan (CAS No. 97682-44-5, sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (CAS No. 119413-54-6, sold under the tradename Hycamtin® by GlaxoSmithKline);

Topoisomerase II inhibitors: etoposide (CAS No. 33419-42-0, also known as VP-

16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), or teniposide (CAS No. 29767-20-2, also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (CAS No. 162635-04-3, sold under the tradename Torisel® by Pfizer), ridaforolimus (CAS No. 572924-54-0, formally known as deferolimus, AP23573 and MK8669, and described in PCT Publication No. WO 03/064383), or everolimus (CAS No. 159351-69-6, sold under the tradename Afmitor® by Novartis);

Proteasome inhibitor such as carfilzomib (CAS No. 868540-17-4), MLN9708 (CAS No. 1201902-80-8), delanzomib (CAS No. 847499-27-8), or bortezomib (CAS No. 179324-69-7);

BET inhibitors such as INCB054329 (CAS No. 1628607-64-6), OTX015 (CAS No. 202590-98-5), or CPI-0610 (CAS No. 1380087-89-7);

LSD1 inhibitors such as GSK2979552, or INCB059872;

HIF-2a inhibitors such as PT2977 (1672668-24-4), NKT2152, or PT2385 (CAS No. 1672665-49-4);

Osteoclastic bone resorption inhibitors: 1 -hydroxy -2-imidazol-l-yl- phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis);

CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename Zevalin®); Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®);

Synthetic Interleukin- 11 (IL-1 1): oprelvekin (sold under the tradename Neumega® by Pfizer/Wyeth);

Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by Amgen);

Receptor Activator for Nuclear Factor k B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen);

Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename

Nplate® by Amgen;

Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen);

Anti-insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6);

Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);

Histone deacetylase inhibitors: Voninostat (sold under the tradename Zolinza® by Merck);

Alkylating agents: Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC -Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSP A, sold under the tradename Thioplex®;

Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), or Denileukin diftitox (sold under the tradename Ontak®);

Anti -turn or antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), or mitomycin C (sold under the tradename Mutamycin®);

Anti -microtubule agents: Estramustine (CAS No. 52205-73-9, sold under the tradename Emcyl®);

Cathepsin K inhibitors: Odanacatib (CAS No. 603139-19-1, also know as MK- 0822 available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836);

Epothilone B analogs: Ixabepilone (CAS No. 219989-84-1, sold under the tradename Lxempra® by Bristol- Myers Squibb);

Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4,261,989), NVP-HSP990 (CAS No. 934343-74-5), AUY922 (CAS No. 747412-49-3), AT13387 (CAS No. 912999-49-6), STA-9090 (CAS No. 888216-25-9), Debio 0932, KW-2478 (CAS No. 819812-04-9), XL888 (CAS No. 1149705-71-4), CNF2024 (CAS No. 848695-25-0), and TAS-116 (CAS No. 1260533-36- 5);

TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline); Anti-mitotic agents: Docetaxel (CAS No. 114977-28-5, sold under the tradename Taxotere® by Sanofi- Aventis); Adrenal steroid inhibitors: aminoglutethimide (CAS No. 125-84-8, sold under the tradename Cytadren®);

Anti-androgens: Nilutamide (CAS No. 63612-50-0, sold under the tradenames Nilandron® and Anandron®), bicalutamide (CAS No. 90357-06-5, sold under tradename Casodex®), or flutamide (CAS No. 13311-84-7, sold under the tradename Fulexin™);

Androgens: Fluoxymesterone (CAS No. 76-43-7, sold under the tradename Halotestin®);

CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, or CDK9) inhibitors including but not limited to: Alvocidib (CAS No. 146426-40-6, pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3- hydroxy-1 -methyl -4-piperidinyl]-4-chromenone, and described in US Patent No. 5,621,002);

CDK2 inhibitor PF-07104091;

CDK4/6 inhibitors: pabociclib (CAS No. 827022-33-3), ribociclib (CAS No. 1211441-98-3), abemaciclib (CAS No. 1231929-97-7), PF-06873600 (CAS No. 2185857- 97-8), NUV-422 and Trilaciclib (CAS No. 1374743-00-6);

CDK7 inhibitors CT7001 (CAS No. 1805789-54-1) and SY-1365 (CAS No. 1816989-16-8);

CDK9 inhibtiors AZD 4573 (CAS No. 2057509-72-3), P276-00 (CAS No. 920113-03-7), AT7519 (CAS No. 844442-38-2), CYC065 (CAS No. 1070790-89-4) or TP-1287;

Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi -Aventis and Lupron® by Abbott Lab);

Taxane anti -neoplastic agents: Cabazitaxel (l-hydroxy-7,10 -dimethoxy-9-oxo- 5,20- epoxytax-1 l-ene-2a, 4, 13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{ [(tert- butoxy)carbonyl]-amino}-2-hydroxy-3-phenylpropanoate), or larotaxel ((2a,3x,4a,5b,7a,10b,13a)- 4,10-bis(acetyloxy)-13-({ (2R,3S)-3-[(tert- butoxycarbonyl)amino]-2-hydroxy-3- phenylpropanoyl}oxy)-l-hydroxy-9-oxo-5,20- epoxy-7,19-cyclotax- 11 -en-2-ylbenzoate); 5HTla receptor agonists: Xaliproden (also known as SR57746, l-[2-(2- naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No. 5,266,573);

HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;

Iron Chelating agents: Deferasinox (CAS No. 201530-41-8, sold under the tradename Exjade® by Novartis);

Anti -metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5 -fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar- U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™), methotrexate (also known as amethopterin, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), or pentostatin (sold under the tradename Nipent®);

Bisphosphonates: Pamidronate (CAS No. 57248-88-1, sold under the tradename Aredia®), zoledronic acid CAS No. 118072-93-8 (sold under the tradename Zorn eta®);

Demethylating agents: 5-azacitidine (CAS No. 320-67-2, sold under the tradename Vidaza®), decitabine (CAS No. 2353-33-5, sold under the tradename Dacogen®);

Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), or paclitaxel (sold under the tradenames Taxol and Onxal™);

Retinoids: Ali tretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13- cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), or bexarotene (sold under the tradename Targretin®);

Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala- Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R, 1 OS, 11 S, 13 S, 14S, 16R, 17R)-9-fluoro-l 1 , 17-dihydroxy- 17-(2- hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9, 10,1 l,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren- 3-one), prednisolone (sold under the tradenames Delta- Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), or methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M- Prednisol® and Solu- Medrol®);

Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin-11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®);

Estrogen receptor downregulators: Fulvestrant (CAS No. 129453-61-8, sold under the tradename Faslodex®);

Anti-estrogens: tamoxifen (CAS No. 10540-29-1, sold under the tradename Novaldex®); or Toremifene (CAS No. 89778-27-8, sold under the tradename Fareston®);

Selective estrogen receptor modulators (SERMs): Raloxifene (CAS No. 84449-90- 1, sold under the tradename Evista®);

Leutinizing hormone releasing hormone (LFfRH) agonists: Goserelin (CAS No. 145781-92-6, sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, CAS No. 595-33-5, sold under the tradename Megace®);

Miscellaneous cytotoxic agents: Arsenic tri oxide (sold under the tradename Trisenox®), or asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);

Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologies) against immune checkpoint molecules such as CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7- H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti- PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP -224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti -PD 1 antibody is pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab). In some embodiments, the anti-PD-Ll small molecule inhibitor is INCB86550.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti- CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MED 10562 or, INCAGNO 1949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MED 16383.

Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene- transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune- modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.

A compound of the invention can also be used in combination with the following adjunct therapies: Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). The disclosure of the PCT applications referred to herein above are incorporated herein by reference in their entirety.

Examples

The following preparations of intermediates and compounds of of the disclosure (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

Synthetic Examples

Intermediate 1

Synthesis of (2 -methylenetetrahydro- lH-pyrrolizin-7a(5H)-yl)m ethanol

Step 1 : ethyl 2 -methyl ene-5-oxotetrahydro-lH-pyrrolizine-7a(5H)-carboxylate

To a stirred mixture of ethyl 5-oxopyrrolidine-2-carboxylate (50.0 g, 318.13 mmol, 1.00 eq.) and 3-chloro-2-(chloromethyl)prop-l-ene (159.0 g, 1272.10 mmol, 4.00 eq.) in THF (300 mL) was added LiHMDS (668 mL, 1.0 M, 668 mmol, 2.10 eq.) dropwise at -40 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at RT, quenched with sat. NH4CI (aq.) at 0-5 °C, and then neutralized to pH = 7 with 1.0 M aqueous HC1. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, and then dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-70%), to afford the title compound (35.0 g, 52.6%) as a yellow oil.

Step 2: ethyl 2-methylene-5-oxotetrahydro-lH-pyrrolizine-7a(5H)-carboxylate

To a stirred solution of ethyl 2-methylidene-5-oxo-tetrahydropyrrolizine-7a- carboxylate (1.0 g, 4.78 mmol, 1.00 eq.) in THF (10 mL) was added 1.0 M LiAlHj in THF (14.4 mL, 14.4 mmol, 3.01 eq.) dropwise at RT under nitrogen atmosphere. The resulting mixture was refluxed for 3 h, cooled and then quenched with MeOH and Na2SO4 IOH2O. The resulting mixture was filtered through a Celite pad and concentrated to afford the title compound.

Intermediate 2

Synthesis of ((2S,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

- n -

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2-

(chloromethyl)allyl)-pyrrolidine- 1 ,2-dicarboxylate

A solution of HMDS (52 g, 320 mmol, 1.15 equiv) in THF (1000 mL) was treated with n-BuLi (128 mL, 320 mmol, 1.15 equiv) for 30 min at -78 °C under nitrogen atmosphere, followed by the addition of 1 -(tert-butyl) 2-m ethyl (2R,4R)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate (100 g, 278 mmol, 1.0 equiv) dropwise at -78 °C. 3-Chloro-2-(chloromethyl)prop-l-ene (87 g, 695 mmol, 2.5 equiv) was added dropwise over 20 min. at -78 °C and the resulting mixture was stirred for additional 12 h at room temperature. The reaction was quenched with NH4CI (aq.) at 5 °C and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA /PE (0-30%) to afford to afford the title compound (87 g).

Step 2: 1 -(tert-butyl) 2-m ethyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine- 1,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2- (2-(chloromethyl)allyl)pyrrolidine-l,2-dicarboxylate (100 g, 223 mmol, 1.0 equiv) in THF (1000 mL) was added TBAF (267 mL, 267 mmol, 1.2 equiv, 1 M in THF) dropwise at room temperature and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE(0-10%) to afford the title compound (65 g). Step 3: 1 -(tert-butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-l,2- dicarboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)- 4-hydroxypyrrolidine-l,2-dicarboxylate (60 g, 180 mmol, 1.0 equiv) in DCM (600 mL) was added BAST (59.6 g, 270 mmol, 1.5 equiv) dropwise at -78 °C. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by adding water and the mixture was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-40%) to afford the title compound (30 g).

Step 4: methyl (2S,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a solution of 1-tert-butyl 2-methyl (2R,4S)-2-[2-(chloromethyl)prop-2-en-l-yl]- 4-fluoropyrrolidine-l,2-dicarboxylate (30 g, 89.3 mmol, 1 equiv.) in DCM (225 mL) was added TFA (75 mL) dropwise at 0 °C and the resulting mixture was stirred for 4 h at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue was basified to pH 8 by adding NH3 solution in MeOH at 0-5 °C. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (16 g). Step 5 : ((2S,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

To a stirred solution of methyl (2S,7aR)-2-fluoro-6-methylenetetrahydro-lH- pyrrolizine-7a(5H)-carboxylate (2 g, 10 mmol, 1 equiv) in THF (20 mL) was added LiAlH4 (10 mL, 10 mmol, 1.0 equiv, 1.0 M in THF) dropwise at 0 °C and the resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with 15% NaOH(aq) and water at 0 °C. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title compound (1.73 g). MS (ES, m/z): [M+H]⁺ = 172.2.

Intermediate 3

Synthesis of ((2R,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-l,2- dicarboxylate

To a stirred solution of 1 -tert-butyl 2-m ethyl (2S,4R)-4-fluoropyrrolidine-l,2- dicarboxylate (40 g, 162 mmol, 1.0 equiv) in THF (400 mL) added LiHMDS (324 mL, 324 mmol, 2.0 equiv, 1.0 M in THF) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 15 min. 3-Chloro-2-(chloromethyl)prop-l-ene (30.4 g, 243 mmol, 1.5 equiv) was added dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred overnight room temperature under nitrogen atmosphere. The reaction was acidified with 1.0 M HC1 aq. solution at 0 °C to pH = 7 and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-10%) to afford the title compound (20 g).

Step 2: methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)- 4-fluoropyrrolidine-l,2-dicarboxylate (20 g, 59.5 mmol, 1 equiv.) in DCM (150 mL) was added TFA (50 mL) dropwise at 0 °C and the resulting mixture was stirred for 4 h at room temperature. The mixture was then concentrated under reduced pressure and the residue was basified to pH 8 with NH3 solution in MeOH at 0-5 °C. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA / PE (0-50%) to afford the title compound (10.7 g). Step 3 : ((2R,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in

Intermediate 2, Step 5, by reducing the ester group with Li AIH4. MS (ES, m/z): [M+H]⁺=172.2.

Intermediate 4

Synthesis of ((2R,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

Step 1 : 1 -(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-

(chloromethyl)allyl)-pyrrolidine- 1 ,2-dicarboxylate

To a stirred solution of HMDS (52 g, 320 mmol, 1.15 equiv) in THF (1000 mL) was added n-BuLi (20 g, 320 mmol, 1.15 equiv) dropwise at -78 °C under nitrogen atmosphere and the resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. 1 -(tert-butyl) 2-Methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-pyrrolidine- 1,2-dicarboxylate (100 g, 278 mmol, 1 equiv.) was added and the resulting mixture was stirred for 15 min at -78 °C under nitrogen atmosphere. 3-Chloro-2-(chloromethyl)prop-l- ene (87 g, 695 mmol, 2.5 equiv) was added to the above solution and the resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0 °C and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10: 1) to afford the title compound (75 g).

Step 2: methyl (2S,7aS)-2-hydroxy-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2- (2-(chloromethyl)allyl)pyrrolidine-l,2-dicarboxylate (60 g, 134 mmol, 1 equiv.) in DCM (450 mL) was added TFA (150 mL) dropwise at 0 °C and the resulting mixture was stirred for 16 h at room temperature. The mixture was concentrated under vacuum and the residue was basified to pH 8 with NH3 solution in MeOH. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%) to afford the title compound (18.8 g).

Step 3: methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a stirred solution of methyl (2S,7aS)-2-hydroxy-6-methylenetetrahydro-lH- pyrrolizine-7a(5H)-carboxylate (1.0 g, 5.1 mmol, 1 equiv.) in DCM (10 mL) was added DAST (1.23 g, 7.6 mmol, 1.5 equiv) dropwise at -78 °C and the resulting mixture was stirred for 2 h at room temperature. The mixture was then extracted with DCM and the combined organic layers were washed with brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (300 mg).

Step 4 : ((2R, 7aS)-2-fluoro-6-methyl enetetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 2, Step 5, by reducing the ester group with LiAlEU. MS (ES, m/z): [M+H]⁺ = 172.1

Intermediate 5

Synthesis of: ((2S,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

Step 1 : 1 -(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-((4-nitrobenzoyl)oxy)- pyrrolidine- 1 ,2-dicarboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4- hydroxypyrrolidine-l,2-dicarboxylate (7.5 g, 22.5 mmol, 1 equiv.), 4-nitrobenzoic acid (4.5 g, 27.0 mmol, 1.2 equiv.) and PPhs (7.1 g, 27.0 mmol, 1.2 equiv) in THF (75 mL) was slowly added DEAD (4.7 g, 27 mmol, 1.2 equiv) at 0 °C. The resulting mixture was allowed to warm to room temperature and then stirred for 1 h at 25 °C under N2 atmosphere. The reaction was quenched with aq. NaHCOs solution at 0 °C and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%) to afford the title compound (5.0 g).

Step 2: methyl (6R,7aS)-2-methylene-6-((4-nitrobenzoyl)oxy)tetrahydro-lH-pyrrolizine- 7 a(5H)-carboxyl ate

A solution of 1 -(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-((4- nitrobenzoyl)oxy)pyrrolidine-l,2-dicarboxylate (11 g, 22.78 mmol, 1.0 equiv.) in DCM (100 mL) was added TFA (50 mL) dropwise at 0 °C and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was then concentrated under vacuum and the residue was neutralized to pH 7 with NH3 solution in MeOH. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with PE/EA (0-20%) to afford the title compound (6.3 g). Step 3: methyl (2R,7aS)-2-hydroxy-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

A mixture of methyl (6R,7aS)-2-methylene-6-((4-nitrobenzoyl)oxy)tetrahydro-lH- pyrrolizine-7a(5H)-carboxylate (5.8 g, 16.7 mmol, 1.0 equiv) and K^CCE (4.63 g, 33.5 mmol, 2.0 equiv) in MeOH (58 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%) to afford the title compound (2.8 g). Step 4: methyl (2S,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a solution of methyl (2R,7aS)-2-hydroxy-6-methylenetetrahydro-lH- pyrrolizine-7a(5H)-carboxylate (2.0 g, 10 mmol, 1 equiv.) in DCM (20 mL) was added BAST (3.37 g, 15 mmol, 1.5 equiv) dropwise at 0°C under N2 atmosphere and the resulting mixture was stirred for 16 h at room temperature. The mixture was basified to pH = 7 with NH3 solution in MeOH and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (0-50%) to afford the title compound (900 mg).

Step 5: ((2S,7aS)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in

Intermediate 2, Step 5, by reducing the ester group with LiAlHj. MS (ES, m/z . [M+H]⁺ =

172.2

Intermediate 6

Synthesis ((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylenetetrahydro-lH- pyrrolizin-7 a(5H)-yl)m ethanol

Stepl : (2S)-tert-butyl 2-(hydroxymethyl)-5-methoxypyrrolidine-l-carboxylate

To a solution of (S)-l -tert-butyl 2-methyl 5-oxopyrrolidine-l,2-dicarboxylate (150 g, 617 mmol) in DCM (900 mL) was added DIBAL-H (1 M, 2.47 L) and the resulting mixture was stirred at -78 °C for 0.5 h, then at 20°C for 2 h. After cooling to 0 °C, methyl alcohol (3000 mL) and 2 M HC1 (5000 mL) were added. The mixture was stirred for 2 h at room temperature and then extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-50%), to afford the title compound (42.0 g, 181 mmol, 36.8% yield) was obtained as a yellow oil. Step 2 : (5S)-tert-butyl 2-cyano-5-(hydroxymethyl)pyrrolidine-l -carboxylate

Boc Boc

To a solution of (2S)-tert-butyl 2-(hydroxymethyl)-5-methoxypyrrolidine-l- carboxylate (48.0 g, 208 mmol) in DCM (500 mL) at -70 °C was added TMSCN (51.5 g, 519 mmol, 64.9 mL) dropwise and then BF3.Et2O (64.8 g, 457 mmol, 56.4 mL). The resulting mixture was then stirred at -70 °C for 1 h and then quenched with sat. NaHCOs aq. solution. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%), to afford the title compound (31.0 g).

Step3 : tert-butyl (2S)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-5-cyano-pyrrolidine-l- carboxylate

To a solution of tert-butyl (5S)-2-cyano-5-(hydroxymethyl)pyrrolidine-l- carboxylate (50 g, 220 mmol, 1 eq) in THF (500 mL) was added imidazole (37.6 g, 552.43 mmol, 2.5 eq) and tert-butyl-chlorodiphenylsilane (66.8 g, 243 mmol, 62.4 mL, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h and then quenched with H2O, and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%), to afford the title compound (69.0 g).

Step 4: (5 S)-l -tert-butyl 2-methyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-l,2- dicarboxylate

A mixture of tert-butyl (2S)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-5-cyano- pyrrolidine-1 -carboxylate (69.0 g, 148 mmol, 1 eq) and K2CO3 (26.6 g, 193 mmol, 1.3 eq) in MeOH (500 mL) was stirred at 50 °C for 12 h under N2 atmosphere. The mixture was acidified with 1.0 M HC1 aq. to pH= 4 and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-15%), to afford the title compound (12 g, 19.53 mmol).

Step 5: 1 -(tert-butyl) 2-methyl (2S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(2- (chloromethyl)allyl)pyrrolidine-l,2-dicarboxylate

To a solution of (5 S)-l -tert-butyl 2-methyl 5-(((tert- butyldiphenylsilyl)oxy)methyl)-pyrrolidine-l,2-dicarboxylate (12.0 g, 24.1 mmol, 1 eq) in THF (100 mL) was added LiHMDS (1 M, 48.22 mL, 2 eq) at -70 °C and the mixture was stirred at -70 °C for 15 min. 3-Chloro-2-(chloromethyl)prop-l-ene (4.52 g, 36.1 mmol, 4.19 mL, 1.5 eq) was added dropwise at -70 °C under nitrogen atmosphere and the resulting mixture was stirred 16 h at 20 °C. The mixture was quenched with sat. NaHCOs aq. and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-10%), to afford the title compound (11 g). Step 6: methyl (5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylenetetrahydro- lH-pyrrolizine-7a(5H)-carboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2S,5S)-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2-(2-(chloromethyl)allyl)pyrrolidine-l,2-dicarboxylate (10.7 g, 18.2 mmol, 1 eq) in DCM (90 mL) was added TFA (45 mL) at 0 °C and the resulting mixture was stirred at 20 °C for 2 h. The reaction was quenched by adding sat. aq. NaHCOs solution at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over ISfeSCU filtered and concentrated. The residue was purified by column chromatography eluted with EA/PE (0-10%), to afford the title compound (3.2 g, crude). Step 7: ((5 S, 7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2 -methyl enetetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol

To a solution of LiAIT (540 mg, 14.2 mmol, 2 eq) in THF (20 mL) was added dropwise methyl (5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2- methylenetetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (3.2 g, 7.12 mmol, 1 eq) in THF (10 mL) at -40 °C and the resulting mixture was stirred at -40 °C for 1 h. After cooling the mixture to 0 °C, the mixture was quenched by adding ISfeSCL. IOH2O. The mixture was then filtered and concentrated under reduced pressure to give the title compound (2.83 g, crude). MS (ESI) m/z = 422.6 [M+l]⁺

Intermediate 7

Synthesis of ((5S,7aS)-5-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylenetetrahydro-

1 H-pyrrolizin-7a(5H)-yl)methanol

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,5S)-5-allylpyrrolidine-l,2-dicarboxylate

O Boc o Boc

To a stirred solution of 1 -(tert-butyl) 2-methyl (2R)-5-methoxypyrrolidine-l,2- dicarboxylate (J. Org. Chem. 2008, 73, 1661) (25 g, 96 mmol, 1 equiv) and allyltrimethylsilane (49.60 g, 434 mmol, 4.5 equiv) in DCM (250 mL) was added TiCL (18.29 g, 96 mmol, 1 equiv) dropwise at -78 °C and the resulting mixture was stirred for 1 h at -78 °C. The reaction mixture was basified to pH=7 with saturated NaHCOs aq. solution. The mixture was filtered and the filtrate was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0- 10%) to afford the title compound (10 g).

Step 2: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-oxoethyl)pyrrolidine-l,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl (2R,5S)-5-(prop-2-en-l-yl)pyrrolidine-l,2- dicarboxylate (10 g, 37 mmol, 1 equiv) in THF (120 mL) and H2O (40 mL) were added K2OSO4.2H2O (1.36 g, 3.7mmol, 0.1 equiv) and NaICU (23.80 g, 111 mmol, 3.0 equiv) at 0 °C. The resulting mixture was stirred for 16 h at room temperature under air atmosphere. The mixture was then filtered and the filter cake was washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with NaEISCh aq. solution and brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (7 g).

Step 3: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-hydroxyethyl)pyrrolidine-l,2-dicarboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-oxoethyl)pyrrolidine- 1,2-dicarboxylate (7 g, 25 mmol, 1 equiv) in MeOH (15 mL) was added NaBEU (1.95 g, 51 mmol, 2 equiv) in portions at 0 °C and the resulting mixture was stirred for 30 min. at 0 °C. The mixture was acidified to pH=6 with 2.0 M HC1 aq. solution and then concentrated under reduced pressure. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0- 50%) to afford the title compound (7 g).

Step 4: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-((tert- butyldiphenylsilyl)oxy)ethyl)pyrrolidine-l,2-dicarboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2- hydroxyethyl)pyrrolidine-l,2-dicarboxylate (7 g, 25 mmol, 1 equiv) and TBDPSC1 (8.45 g, 30 mmol, 1.2 equiv) in DCM (150 mL) was added imidazole (2.62 g, 38 mmol, 1.5 equiv) in portions at room temperature and the resulting mixture was stirred for 2 h at room temperature. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with THF/PE (0-10%) to afford the title compound (7.0 g).

Step 5: ((5S,7aS)-5-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylenetetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 6, Steps 5-7, using 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-((tert- butyldiphenylsilyl)oxy)-ethyl)pyrrolidine-l,2-dicarboxylate instead of (5 S)-l -tert-butyl 2- methyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-l,2-dicarboxylate in Step 5.

Intermediate 8

Synthesis of ((4aS,8aR,9aS)-hexahydro-lH,3H-pyrano[3,4-b]pyrrolizin-8a(6H)- yl)methanol [Int-8a] and ((4aR,8aS,9aR)-hexahydro-lH,3H-pyrano[3,4-b]pyrrolizin-

8a(6H)-yl)methanol [Int-8b]

Step 1 : 7a-(tert-butyl) 2-methyl (2S,3S,7aR)-3-(2-(benzyloxy)ethyl)tetrahydro-lH- pyrrolizine-2,7a(5H)-dicarboxylate and 7a-(tert-butyl) 2-methyl (2R,3R,7aS)-3-(2- (benzyloxy)ethyl)-tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate

To a stirred solution of tert-butyl L-prolinate (15.0 g, 87.6 mmol, 1.0 eq.) in toluene (600 mL) was added silver acetate (0.73 g, 4.4 mmol, 0.050 eq.) in one portion, 3- (benzyloxy)propanal (14.4 g, 87.7 mmol, 1.0 eq.), methyl acrylate (7.5 g, 87.1 mmol, 1.0 eq.) and triethylamine (9.8 g, 96.8 mmol, 1.1 eq.) at room temperature.. After stirring at room temperature for 16 h under dark, the reaction mixture was concentrated. The residue was purified twice by silica gel column chromatography, eluted with EA / PE (0-30%), to afford the title compounds (2.3 g, 6.5%) as a light-yellow oil.

Step 2: tert-butyl (2S,3S,7aR)-3-(2-(benzyloxy)ethyl)-2-(hydroxymethyl)tetrahydro-lH- pyrrolizine-7a(5H)-carboxylate and tert-butyl (2R,3R,7aS)-3-(2-(benzyloxy)ethyl)-2- (hydroxymethyl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate

To a stirred solution of 7a-(tert-butyl) 2-methyl (2S,3S,7aR)-3-(2- (benzyloxy)ethyl) tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate and 7a-(tert-butyl) 2- methyl (2R,3R,7aS)-3-(2-(benzyloxy)ethyl) tetrahydro- lH-pyrrolizine-2,7a(5H)- dicarboxylate (1.5 g, 3.7 mmol, 1.0 eq.) in THF (15 mL) was added DIBAL-H (7.5 mL, 7.5 mmol, 1.0 M, 2.0 eq.) dropwise at 5 °C under nitrogen atmosphere. After stirring for 30min, additional DIBAL-H (3.7 mL, 3.7 mmol, 1.0 M, 1.0 eq.) was added dropwise. The reaction mixture was quenched with water, diluted with THF, and then the addition of Na2SO4- IOH2O. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated to remove most organic solvent, and the resulting aqueous residue was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous ISfeSCU, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%), to afford the title compounds (600 mg, 43.2%) as a light-yellow oil.

Step 3: tert-butyl (2S,3S,7aR)-3-(2-hydroxyethyl)-2-(hydroxymethyl)tetrahydro-lH- pyrrolizine-7a(5H)-carboxylate and tert-butyl (2R,3R,7aS)-3-(2-hydroxyethyl)-2- (hydroxymethyl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate

A mixture of tert-butyl (2S,3S,7aR)-3-(2-(benzyloxy)ethyl)-2-(hydroxymethyl) tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate and tert-butyl (2R,3R,7aS)-3-(2- (benzyloxy)ethyl)-2-(hydroxymethyl) tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (350 mg, 0.93 mmol, 1.0 eq.), HCl(g) in MeOH (50 mg) and 10% Pd/C (525 mg) in MeOH (17.5 mL) was stirred for 16 h at 50 °C under 20 atm hydrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-20%), to afford the titles compound (150 mg, 57.0%) as a light yellow oil.

Step 4: tert-butyl (4aS,8aR,9aS)-hexahydro-lH,3H-pyrano[3,4-b]pyrrolizine-8a(6H)- carboxylate and tert-butyl (4aR,8aS,9aR)-hexahydro-lH,3H-pyrano[3,4-b]pyrrolizine- 8 a(6H)-carb oxyl ate

To a stirred solution of tert-butyl (2S,3S,7aR)-3-(2-hydroxyethyl)-2- (hydroxymethyl)-tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate tert-butyl (2R,3R,7aS)-3- (2-hydroxyethyl)-2-(hydroxymethyl)tetrahydro- lH-pyrrolizine-7a(5H)-carboxylate (150 mg, 0.53 mmol, 1.0 eq.) in THF (4.5 mL) was added 60% sodium hydride (74 mg, 1.85 mmol, 3.5 eq.) in portions at 5 °C under nitrogen atmosphere, followed by a solution of methanesulfonyl chloride (60 mg, 0.52 mmol, 1.0 eq.) in THF (0.5 mL) dropwise at 5 °C. The resulting mixture was stirred for additional 16 h at room temperature, quenched with water at 5 °C, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%), to afford the title compounds (60 mg, 42.3%) as a light-yellow oil.

Step 5: ((4aS,8aR,9aS)-hexahydro-lH,3H-pyrano[3,4-b]pyrrolizin-8a(6H)-yl)methanol and ((4aR,8aS,9aR)-hexahydro-lH,3H-pyrano[3,4-b]pyrrolizin-8a(6H)-yl)methanol

lnt-8a lnt-8b

The title compound was prepared by proceeding analogously as described in Intermediate 1, Step 2, by reducing the ester group with LiAlEU. MS (ES, m/z): [M+H]⁺ = 198.2.

Intermediate 9

Synthesis of (2,3-dihydro-lH-pyrrolo[2, l-a]isoindol-9b(5H)-yl)m ethanol

A solution of methyl prolinate (5.0 g, 38.71 mmol, 1.00 eq.) and 2- bromobenzaldehyde (14.32 g, 77.40 mmol, 2.00 eq.) in DCM (50 m ) was stirred at 25 °C for 1 h. To this solution was added NaBH(OAc)3 (16.41 g, 77.43 mmol, 2.00 eq.) in portions at 5 °C, and the resulting mixture was stirred at 25°C for 5h. The reaction mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (9/1), to afford the title compound (4.5 g, 39.0%) as a colorless oil.

Step 2: tert-butyl 2,3-dihydro-lH-pyrrolo[2,l-a]isoindole-9b(5H)-carboxylate

A mixture of t-BuOLi (2.35 g, 29.34 mmol, 3.50 eq.), DavePhos (0.16 g, 0.42 mmol, 0.05 eq.) and Pd2(dba)3 (0.15 g, 0.17 mmol, 0.02 eq.) in 1,4-di oxane (25 mL) was stirred at 25 °C for 5 min under N2 atmosphere. To this mixture were added dodecane (0.43 g, 2.52 mmol, 0.30 eq.) and methyl (2-bromobenzyl)prolinate (2.5 g, 8.38 mmol, 1.00 eq.) at 25 °C. The resulting mixture was stirred at 85 °C for 12 h under N2 atmosphere, diluted with water and then extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/5), to afford the title compound (1.1 g, 50.6%) as a light- yellow solid. Step 3 : (2,3-dihydro-lH-pyrrolo[2, l-a]isoindol-9b(5H)-yl)methanol

To a stirred solution of tert-butyl 2,3-dihydro-lH-pyrrolo[2,l-a]isoindole-9b(5H)- carboxylate (1.0 g, 3.86 mmol, 1.00 eq.) in THF (1.0 mL) was added 1.0 M LiAlEL in THF (5.8 mL, 5.8 mmol, 1.50 eq.) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at 0 °C for Ih, quenched with water, 15% aqueous NaOH and then water in sequence at 0 °C. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated to give the title compound (369.7 mg, 50.6%) as a light-yellow solid..

Intermediate 10

Synthesis of ((5 S,7aS)-5-(l -((tert-butyl diphenylsilyl)oxy)ethyl)-2-methylenetetrahydro-

1 H-pyrrolizin-7a(5H)-yl)methanol

Stepl : (2S)-tert-butyl 2-(hydroxymethyl)-5-methoxypyrrolidine-l-carboxylate

To a solution of (S)-l -tert-butyl 2-methyl 5-oxopyrrolidine-l,2-dicarboxylate (20 g, 82.3 mmol, 1.0 equiv) in DCM (200 mL) was added DIBAL-H (1 M, 329.2 mL) at -78 °C and the resulting mixture was stirred at -78 °C for 0.5 hrs and at 20 °C for 2 h. After cooling to 0 °C, to the above solution were added methyl alcohol (320 mL) and 2.0 M HC1 aq. solution (320 mL) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-50%), to afford the title compound (14.0 g)-

Step 2 '■ tert-butyl (2S)-2-formyl-5-methoxypyrrolidine-l-carboxylate

To a solution of tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-l- carboxylate (9.0 g, 38.9 mmol, 1 eq) in DCM (90 mL) was added Dess-Martin periodinane (19.8 g, 46.7 mmol, 1.2 eq) and the resulting mixture was stirred at 25 °C for 12 h. The mixutre was quenched with sat. NaHCOs aq. solution. The mixture was filtrated and the filtratewas diluted with water, and then extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, and the residue was purified by column chromatography, eluted with EA/PE (0-25%) to afford the title compound (4.9 g).

Step 3 '• tert-butyl (2S)-2-(l-hydroxyethyl)-5-methoxypyrrolidine-l-carboxylate

B

To a solution of tert-butyl (2S)-2-formyl-5-methoxypyrrolidine-l -carboxylate (4.9 g, 21.4 mmol, 1.0 eq) in THF (50 mL) was added dropwise CEEMgCl in THF (3.0 M, 64.1mmol, 21.4 mL, 3.0 eq) at 0 °C and the resulting mixture was stirred at 25 °C for 1 h. After coolign to 0 °C, the mixture was quenched by adding sat. NH4CI aq. solution at 0 °C and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%), to afford the title compound (3.7 g). Step 3 '• tert-butyl (5 S)-2-cyano-5-(l -hydroxy ethyl)pyrrolidine-l -carboxylate

To a solution of tert-butyl (2S)-2-(l-hydroxyethyl)-5-methoxypyrrolidine-l- carboxylate (3.7 g, 15.1 mmol, 1.0 eq) in DCM (35 mL) was added dropwise TMSCN (3.7g, 37.7 mmol, 2.5 eq) at -70 °C and then BF3.Et2O (4.7g, 33.2 mmol, 2.2 eq) at -70 °C. The resulting mixture was stirred at -70 °C for 1 h. After warming to 0 °C, the mixture was quenched with sat. NaHCOs aq. solution and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0- 30%), to afford the title compound (2.7 g).

Step 4: 1 -(tert-butyl) 2-methyl (5S)-5-(l-hydroxyethyl)pyrrolidine-l,2-dicarboxylate

A mixture of tert-butyl (5S)-2-cyano-5-(l-hydroxyethyl)pyrrolidine-l-carboxylate (2.7 g, 11.2 mmol, 1 eq), K2CO3 (3.1g, 22.5 mmol, 2.0 eq) in MeOH (25 mL) was stirred at 25 °C for 3 h under N2 atmosphere. The mixture was quenched with 1.0 M HC1 aq. solution to pH= 2 and then stirred at 25 °C overnight. The mixture was basified to pH=8 by adding sat. NaHCOs aq. solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-35%) to afford the title compound (1.6 g).

Step 5: 1 -(tert-butyl) 2-methyl (5S)-5-(l-((tert-butyldiphenylsilyl)oxy)ethyl)pyrrolidine 1,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (5S)-5-(l-hydroxyethyl)pyrrolidine-l,2- dicarboxylate (1.6 g, 5.9 mmol, 1.0 eq) in DMF (2 mL) was added imidazole (1.2 g, 17.6 mmol, 3.0 eq) and tert-butyl-chlorodiphenylsilane (3.2 g, 11.7 mmol, 2.0 eq) at 0 °C and the resulting mixture was stirred at 20 °C for 12 h. The mixutre was quenched with waterand extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%) to afford crude compound. The crude compound was purified by reverse column to afford the title compound (2.6 g) as a colorless oil.

Step 6: ((5S,7aS)-5-(l-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylenetetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in

Intermediate 6, Steps 5-7, using 1 -(tert-butyl) 2-methyl (5S)-5-(l-((tert- butyldiphenylsilyl)oxy)ethyl) pyrrolidine- 1,2-dicarboxylate instead of (5 S)-l -tert-butyl 2-methyl 5-(((tert- butyldiphenylsilyl)-oxy)methyl)pyrrolidine-l,2-di carboxylate in Step 5.

Intermediate 11

Synthesis of (2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

Step 1 : ethyl-2-(fluoromethylene)-5-oxotetrahydro-lH-pyrrolizine-7a(5H)-carboxylate

To a stirred mixture of (fluorom ethyl )triphenylphosphanium tetrafluoroborate (3.6 g, 9.42 mmol, 2.49 eq.) in THF (26 mL) was added n-BuLi (3.8 mL, 2.5 M, 9.50 mmol, 2.51 eq.) dropwise at -78 °C under nitrogen atmosphere. After stirring for 1 h at -78 °C, a solution of ethyl 2,5-dioxo-tetrahydropyrrolizine-7a-carboxylate (800 mg, 3.79 mmol, 1.00 eq.) in THF (30 mL) was added dropwise over 10 min at -78 °C. The resulting mixture was warmed and stirred overnight at RT. The reaction mixture was quenched with saturated NH4CI (aq.) at RT, diluted with water, and then extracted with EtOAc. The combined organic layer was concentrated and then purified by silica gel column chromatography, eluted with PE/EA (5:2), to afford the title compound (100 mg, 11.6%) as a colorless oil.

Step 2: (2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

To a stirred solution of ethyl-2-(fluoromethylene)-5-oxotetrahydro-lH-pyrrolizine- 7a(5H)-carboxylate (80 mg, 0.35 mmol, 1.00 eq.) in THF (0.80 mL) was added a solution of LiAlEU in THF (0.70 mL, 2.0 M, 1.40 mmol, 4.00 eq.) slowly at 0 °C under nitrogen atmosphere. The resulting mixture was refluxed for 3h at 70°C under nitrogen atmosphere, cooled and then was added ISfeSCU. The resulting mixture was quenched by addition of water, filtered and the solid cake was washed with THF. The filtrate was concentrated to afford the title compound (70 mg) as a colorless oil.

Intermediate 12

Synthesis of (2-(2,2-difluoroethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

Step 1 : ethyl 2-(2,2-difluoroethylidene)-5-oxotetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

A mixture of Ir(ppy)3 (75 mg, 0.115 mmol, 0.03 eq.), CuBn (171 mg, 0.765 mmol, 0.2 equiv), (difluoromethyl)triphenylphosphonium bromide (4.51 g, 11.499 mmol, 3.00 eq.) and ethyl 2-methylidene-5-oxo-tetrahydropyrrolizine-7a-carboxylate (800 mg, 3.823 mmol, 1.00 eq.) in DMF (5 mL) was degassed for three times by the freeze-pump-thaw procedure. The reaction mixture was irradiated with blue LEDs for 10 h, and then was added DBU (3.49 g, 22.924 mmol, 6.00 eq.). After stirring for lOh, the reaction mixture was poured into brine, extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel to give the title compound (380 mg, 38.3%) as a lightyellow solid.

Step 2: (2-(2,2-difluoroethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

To a stirred solution of ethyl 2-(2,2-difluoroethylidene)-5-oxotetrahydro-lH- pyrrolizine-7a(5H)-carboxylate (300 mg, 1.157 mmol, 1.00 eq.) in THF (3.0 mL) was charged with 2.0 M LiAlHj in THF (2.3 mL, 4.60 mmol, 3.98 eq.) over 10 min at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 0°C, and then refluxed for 3h. To the cooled reaction mixture was added Na2SO4, followed by water slowly at RT. The resulting mixture was filtered and the solid cake was washed with THF. The filtrate was concentrated to afford the title compound (230 mg, 97.8%) as a colorless oil. MS (ES, m/zy. [M+l]⁺ = 228.2..

Intermediate 13

Synthesis of ((3aR,7aR,8aS)-hexahydro-lH-furo[3,4-b]pyrrolizin-7a(5H)-yl)methanol and

((3aS,7aS,8aR)-hexahydro-lH-furo[3,4-b]pyrrolizin-7a(5H)-yl)methanol

Step 1 : 2-(tert-butyl) 7a-methyl (2S,3R,7aR)-3-((benzyloxy)methyl)tetrahydro-lH- pyrrolizine-2,7a(5H)-dicarboxylate and 2-(tert-butyl) 7a-methyl (2R,3S,7aS)-3- ((benzyloxy)methyl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate

To a stirred solution of methyl L-prolinate hydrochloride (22.0 g, 132.83 mmol, 1.00 eq.) in toluene (800 mL) were added AgOAc (1.11 g, 6.65 mmol, 0.050 eq.), 2- (benzyloxy) acetaldehyde (19.95 g, 132.84 mmol, 1.00 eq.), tert-butyl acrylate (17.00 g, 132.64 mmol, 1.00 eq.) and triethylamine (14.79 g, 146.16 mmol, 1.10 eq.) at RT. After stirring at RT for 16 h under dark condition, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%), to afford the title compound (2.50 g, 4.8%) as a light -yellow oil.

Step 2: 2-(tert-butyl) 7a-methyl (2S,3R,7aR)-3-(hydroxymethyl)tetrahydro-lH- pyrrolizine-2,7a(5H)-dicarboxylate and 2-(tert-butyl) 7a-methyl (2R,3S,7aS)-3- (hydroxymethyl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate

A mixture of 2-(tert-butyl) 7a-methyl (2S,3R,7aR)-3- ((benzyloxy)methyl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate and 2-(tert-butyl) 7 a-methyl (2R,3 S, 7aS)-3 -((benzyl oxy)-m ethyl )tetrahydro- 1 H-pyrrolizine-2, 7 a(5H)- dicarboxylate (2.40 g, 6.16 mmol, 1.00 eq.), HC1 (g) in MeOH (1 drop) and 10% Pd/C (7.20 g) in MeOH (240 mL) was stirred for 16 h at 50 °C under hydrogen atmosphere (20 atm). The reaction mixture was basified to pH = 9 with ammonia aqueous solution. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, eluted with MeOH/CTbCh (0-10%), to afford the title compound (900 mg, 48.9%) as a yellow oil.

Step 3: 2-(tert-butyl) 7a-methyl (2S,3R,7aR)-3-((tosyloxy)methyl)tetrahydro-lH- pyrrolizine-2,7a(5H)-dicarboxylate and 2-(tert-butyl) 7a-methyl (2R,3S,7aS)-3- ((tosyloxy)methyl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate

To a stirred solution of 2-(tert-butyl) 7a-methyl (2S,3R,7aR)-3-(hydroxymethyl) tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate and 2-(tert-butyl) 7a-methyl (2R,3S,7aS)-3-(hydroxymethyl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate (900 mg, 3.01 mmol, 1.00 eq.), DMAP (73 mg, 0.60 mmol, 0.20 eq.) and triethylamine (608 mg, 6.01 mmol, 2.00 eq.) in DCM (18 mL) was added a solution of p-toluenesulfonyl chloride (745 mg, 3.91 mmol, 1.30 eq.) in DCM (3.6 mL) dropwise at 5 °C. The resulting mixture was stirred at RT for 2 h, concentrated and then purified by silica gel column chromatography, eluted with EA/PE (0-50%), to afford the title compound (900 mg, 65.8%) as a colorless oil.

Step 4: ((2S,3R,7aR)-2,7a-bis(hydroxymethyl)hexahydro-lH-pyrrolizin-3-yl)methyl 4- methylbenzenesulfonate and ((2R,3S,7aS)-2,7a-bis(hydroxymethyl)hexahydro-lH- pyrrolizin-3-yl)methyl 4-methylbenzenesulfonate

To a stirred solution of 2-(tert-butyl) 7a-methyl (2S,3R,7aR)-3-((tosyloxy)methyl) tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate and 2-(tert-butyl) 7a-methyl (2R,3S,7aS)-3-((tosyloxy)methyl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate (760 mg, 1.68 mmol, 1.00 eq.) in THF (5.0 mL) was added 1.0 M LiAlHj in THF (5.0 mL, 5.00 mmol, 2.98 eq.) dropwise at 5 °C. After stirring at 5°C for additional Ih, the reaction mixture was diluted with THF, added ISfeSCU, quenched with water at 5 °C. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated to afford the crude title compound (450 mg, 75.6%) as a colorless oil, which was used for next step without further purification.

Step 5: ((3aR,7aR,8aS)-hexahydro-lH-furo[3,4-b]pyrrolizin-7a(5H)-yl)methanol and ((3aS,7aS,8aR)-hexahydro-lH-furo[3,4-b]pyrrolizin-7a(5H)-yl)methanol

To a stirred solution of ((2S,3R,7aR)-2,7a-bis(hydroxymethyl)hexahydro-lH- pyrrolizin-3-yl)methyl 4-methylbenzenesulfonate and ((2R,3S,7aR)-2,7a- bis(hydroxymethyl)hexahydro-lH-pyrrolizin-3-yl)methyl 4-methylbenzenesulfonate (450 mg, 1.27 mmol, 1.00 eq.) in THF (12 mL) was added 60% sodium hydride (152 mg, 3.80 mmol, 3.00 eq.) in portions at 5 °C. The resulting mixture was stirred at RT for 40 h. This reaction mixture was used for next step directly without further purification. Intermediate 14

Synthesis of (2,3-dihydro-lH-pyrrolo[l,2-a]indol-9a(9H)-yl)methanol

Step 1 : 1 -(tert-butyl) 2-ethyl lH-indole-l,2-dicarboxylate

To a stirred solution of ethyl lH-indole-2-carboxylate (30.0 g, 158.66 mmol, 1.00 eq.) and DMAP (3.87 g, 31.68 mmol, 0.20 eq.) in CH3CN (400 mL) was added a solution of BOC2O (69.2 g, 317.07 mmol, 2.00 eq.) in CH3CN (200 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 3h at RT, concentrated and then purified by silica gel column chromatography, eluted with PE/EA (7: 1), to afford the title compound (38.1 g, 83.0%) as a white solid.

Step 2: 1 -(tert-butyl) 2-ethyl indoline- 1,2-dicarboxylate

A mixture of 1 -(tert-butyl) 2-ethyl IH-indole- 1,2-dicarboxylate (38.1 g, 131.68 mmol, 1.00 eq.) and 10% Pd/C (3.8 g) in EtOH (380 mL) was stirred for 6 h at RT under hydrogen atmosphere (1 atm). The reaction mixture was filtered and concentrated to give the title compound (37.0 g, 96.4%) as an off-white solid.

Step 3: 1 -(tert-butyl) 2-ethyl 2-(3 -chi oropropyl)indoline- 1,2-dicarboxylate

To a stirred solution of 1 -(tert-butyl) 2-ethyl indoline- 1,2-dicarboxylate (15.0 g, 51.48 mmol, 1.00 eq.) in THF (300 mL) was added 1.0 M LiHMDS in THF (77 mL, 77 mmol, 1.50 eq.) dropwise at -78 °C under nitrogen atmosphere. After stirring for 30 min, 1 -chi oro-3 -bromopropane (40.5 g, 257.24 mmol, 5.00 eq.) was added dropwise at -78 °C. The resulting mixture was warm to RT and then stirred overnight. The reaction mixture was quenched with saturated NH4CI (aq.) and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-30%), to afford the title compound (10.0 g, 52.8%) as a yellow oil. Step 4: ethyl 2-(3-chloropropyl)indoline-2-carboxylate

A mixture of 1 -(tert-butyl) 2-ethyl 2-(3-chloropropyl)indoline-l,2-di carboxylate (10.0 g, 27.18 mmol, 1.00 eq.) in TFA (100 mL) was stirred for 30 min at RT. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with EA/PE(0-70%), to afford the title compound (7.0 g, 96.2%) as a yellow oil.

Step 5: ethyl 2,3-dihydro-lH-pyrrolo[l,2-a]indole-9a(9H)-carboxylate

A mixture of ethyl ethyl 2-(3-chloropropyl)indoline-2-carboxylate (1.50 g, 5.60 mmol, 1.00 eq.) and K2CO3 (3.87 g, 28.00 mmol, 5.00 eq.) in EtOH (30 mL) was stirred for 2 h at RT. The resulting mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and then concentrated to give the title compound (1.02 g, 78.8%) as a yellow oil.

Step 6: (2,3-dihydro-lH-pyrrolo[l,2-a]indol-9a(9H)-yl)methanol

To a stirred solution of ethyl 2,3-dihydro-lH-pyrrolo[l,2-a]indole-9a(9H)- carboxylate (1.0 g, 4.32 mmol, 1.00 eq.) in THF (10 mL) was added 1.0 M LiAlEL in THF (5.2 mL, 5.2 mmol, 1.20 eq.) dropwise at RT. The resulting mixture was stirred for 2 h at RT, quenched by addition of MeOH and ISfeSCh- IOH2O. The resulting mixture was filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with CFBCL/MeOH (10: 1), to afford the title compound (450 mg, 55.1%) as a yellow oil..

Intermediate 15

Synthesis of ((6R,7aR)-2-ethylidene-6-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

Step 1 : methyl (6R,7aR)-2-ethylidene-6-fluorotetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

A tube was charged with of methyl (2R,7aR)-2-fluoro-6-methylidene-tetrahydro- lH-pyrrolizine-7a-carboxylate (2.5 g, 12.55 mmol, 1.0 equiv), Grubbs 2^nd generation catalyst (3.2 g, 3.76 mmol, 0.3 equiv) and DCM (50 m ). Propylene gas was bubbled into the mixture at 0°C for 10 min. The tube was then sealed and stirred overnight at 40 °C. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%). The product was further purified by prep-HPLC to afford the title compound (1 g) as a brown oil. Step 2: ((6R,7aR)-2-ethylidene-6-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 1, Step 2, by reducing the ester group with 1.0 equiv of LiAlELj. MS (ES, m/z) [M+H]⁺ =186.2

Intermediate 16

Synthesis of ((6S,7aR)-2-cyclobutylidene-6-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 15, Steps 1-2, using methyl (2S,7aR)-2-fluoro-6-methylenetetrahydro-lH- pyrrolizine-7a(5H)-carboxylate and methylenecyclobutane instead of methyl (2R,7aR)-2- fluoro-6-methylidene-tetrahydro-lH-pyrrolizine-7a-carboxylate and propylene in Step 1. MS (ES, m/z): [M+H]⁺ = 212.2.

Intermediate 17

Synthesis of ((6R,7aR)-2-cyclobutylidene-6-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 15, Steps 1-2, using methylenecyclobutane instead of propylene in Step 1. MS (ES, m/z): [M+H]⁺= 212.2.

Intermediate 18

Synthesis of ((2R,7aR)-2-fluoro-6-(propan-2-ylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)- methanol

The title compound was prepared by proceeding analogously as described in Intermediate 15, Steps 1-2, using 2-methylprop-l-ene instead of propylene in Step 1. MS (ES, m/z): [M+H]⁺= 200.2.

Intermediate 19

Synthesis of ((2S,7aS)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

Step 1 : 1 -(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-

1,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-[2- (chloromethyl)prop-2-en-l-yl]pyrrolidine-l,2-dicarboxylate (25 g, 56 mmol, 1 equiv) in THF (250 mL) was added TBAF (18 g, 67 mmol, 1.2 equiv) at room temperature and the resulting mixture was stirred for 2 h at room condition. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PEZEA (5: 1) to afford the title compound (15 g).

Step 2: 1 -(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-methoxypyrrolidine- 1,2-dicarboxylate

A mixture of 1 -(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxy- pyrrolidine- 1,2-dicarboxylate (2.6 g, 7.8 mmol, 1.0 equiv), CH3I (2.2 g, 15.6 mmol, 2.0 equiv) and Ag2O (9.0 g, 39 mmol, 5.0 equiv) in acetone (30 mL) was stirred overnight at room temperature. The reaction mixture was filtered and the filter cake was washed with acetone. The filtrate was concentrated under reduced pressure to give the title compound (2-3 g).

Step 3: methyl (2S,7aS)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-methoxy- pyrrolidine-l,2-dicarboxylate (2.3 g, 6.6 mmol, 1.0 equiv) in DCM (25 mL) was added TFA (8 mL) dropwise at 0-5 °C and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was basified to pH = 8 with NH3 solution in MeOH. The volatile solvents were removed under vacuum and the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford the title compound (880 mg).

Step 4: ((2S,7aS)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 2, Step 5, by reducing the ester group with Li AIH4. MS (ES, m/z): [M+Na]⁺= 206.2

Intermediate 20

Synthesis of ((2R,7aR)-2-methoxy-6-methylenetetrahydro- lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 19, Steps 2-6, using 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2- (chloromethyl)allyl)-4-hydroxypyrrolidine-l,2-dicarboxylate instead of 1 -(tert-butyl) 2- methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-l,2-dicarboxylate in Step 2. MS (ES, m/z): [M+H]+ = 184.2

Intermediate 21

Synthesis of ((2R,7aS)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

Step 1 : 1 -(tert-butyl) 2-m ethyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine- 1,2-dicarboxylate

A mixture of 1 -(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-((4-nitro- benzoyl)oxy)pyrrolidine-l,2-dicarboxylate (4.8 g, 10 mmol, 1 equiv) and LiOH.EEO (1.2 g, 50 mmol, 5 equiv.) in THF (50 m ) was stirred for 1 h at 50 °C. After cooling to room temperature, the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous ISfeSCU and concentrated. The crude product (2.9 g) was used in the next step immediately without further purification. Step 2: ((2R,7aS)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 19, Steps 2-4, using 1 -(tert-butyl) 2-methyl (2S,4R)-2-(2- (chloromethyl)allyl)-4-hydroxypyrrolidine-l,2-dicarboxylate instead of 1 -(tert-butyl) 2- methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-l,2-dicarboxylate in Step 2. MS (ES, m/z): [M+H]⁺= 184.2.

Intermediate 22

Synthesis of ((2S,7aR)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

Step 1 : 1 -(tert-butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-((4-nitrobenzoyl)oxy)- pyrrolidine- 1 ,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4- hydroxy-pyrrolidine-l,2-dicarboxylate (13 g, 39 mmol, 1.0 equiv.) in THF (140 mL) was added 4-nitrobenzoic acid (7.8 g, 47 mmol, 1.2 equiv), PPhs (12.26 g, 46.733 mmol, 1.2 equiv), and DEAD (8.1 g, 47 mmol, 1.2 equiv). The resulting mixture was stirred for 3 h at room temperature under N2 atmosphere. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous ISfeSCE and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%) to afford the title compound (13.5 g)-

Step 2: 1 -(tert-butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine- 1,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-((4- nitrobenzoyl)oxy)pyrrolidine-l,2-dicarboxylate (6.5 g, 13.5 mmol, 1.0 equiv.) in THF (65 mL) was added Li OH (6.5 g, 270 mmol, 20 equiv.) and the resulting mixture was stirred for 6 h at room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude material was used in the next step without further purification.

Step 3 : ((2S,7aR)-2-methoxy-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 19, Steps 2-4, using 1 -(tert-butyl) 2-methyl (2R,4S)-2-(2- (chloromethyl)allyl)-4-hydroxypyrrolidine-l,2-dicarboxylate instead of 1 -(tert-butyl) 2- methyl (2S,4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-l,2-dicarboxylate in Step 2. MS (ES, m/z): [M+H]⁺= 184.1.

Intermediate 23

Synthesis of ((2R,7aR)-2-(difluoromethoxy)-6-methylenetetrahydro- IH-pyrrolizin- 7a(5H)-yl)methanol

Step 1. 1 -(tert-butyl) 2-methyl (2R,4R)-4-(difluorom ethoxy )pyrrolidine-l,2-dicarboxylate

OH OCF₂H

°^ I N t^Z

OMe Boc MeO Boc

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (25.0 g, 102 mmol, 1.0 equiv) and Cui (3.9 g, 20 mmol, 0.2 equiv) in MeCN (270 mL) was added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (21.8 g, 122 mmol, 1.2 equiv) in MeCN (100 mL) dropwise at 50 °C under nitrogen atmosphere and the resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was then cooled at 0 °C and quenched with saturated sodium hyposulfite aq. solution. The mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (18 g). Step 2: ((2R,7aR)-2-(difluoromethoxy)-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared analogously by proceeding as described in Intermediate 3, Steps 1-3 using 1 -(tert-butyl) 2-m ethyl (2R,4R)-4- (difluoromethoxy)pyrrolidine-l,2-dicarboxylate instead of 1 -tert-butyl 2-methyl (2S,4R)- 4-fluoropyrrolidine-l,2-dicarboxylate in Step 1. MS (ES, m/z): [M+H]⁺ = 184.2.

Intermediate 24

Synthesis of ((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)-m ethanol and ((5 S,7aR)-5-(methoxymethyl)-2-methylenetetrahydro- IH-pyrrolizin- 7a(5H)-yl)-methanol

Step 1 : tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-l-carboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-l,2- dicarboxylate (100 g, 411 mmol, 1.0 equiv) in DCM (1500 mL) was added 1.0 M DIBA1- H in toluene (1644 mL, 1644 mmol, 4.0 equiv.) dropwise at -78°C under nitrogen atmosphere and the resulting mixture was stirred for 30 min. at -78 °C. The mixture was then allowed to warm to room temperature and stirred for 2 h at room temperature. After cooling to 0 °C, the mixture was quenched with MeOH and 2 M HC1 dropwise at 0 °C. The mixture was stirred for 2 h at room temperature and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (20-80%) to afford the title compound (45 g).

Step 2: tert-butyl (5 S)-2-methoxy-5-(methoxymethyl)pyrrolidine-l -carboxylate

Boc Boc

To a solution of tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-l- carboxylate (36.0 g, 15.6 mmol, 1.0 equiv.) in DMF (120 mL) was added NaH (12.5 g, 31.2 mmol, 2.0 equiv., 60%) in portions for 15 min. at 0 °C, followed by the addition of CH3I (44.3 g, 31.2 mmol, 2.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred for 2 h and then quenched with water. The mixture was extracted with EtOAc and the

- I l l - combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EAc/PE (0-50%) to afford the title compound (22.5 g).

Step 3: tert-butyl (5S)-2-cyano-5-(methoxymethyl)pyrrolidine-l-carboxylate

A solution of tert-butyl (5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-l- carboxylate (22.5 g, 91.7 mmol, 1.0 equiv) in DCM (220 mL) was treated with TMSOTf (30.6 g, 137.5 mmol, 1.5 equiv) for 15 min. at 0°C, followed by the addition of trimethyl silyl cyanide (13.6 g, 137.5 mmol, 1.5 equiv.) dropwise at 0 °C. The mixture was stirred for 2 h at 0 °C and then quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (10-30%), to afford the title compound (19 g).

Step 4: 1 -(tert-butyl) 2-methyl (5S)-5-(methoxymethyl)pyrrolidine-l,2-dicarboxylate

A solution of tert-butyl (5 S)-2-cyano-5-(methoxymethyl)pyrrolidine-l -carboxylate (13.5 g, 56.2 mmol, 1.0 equiv) and K2CO3 (7.8 g, 56.2 mmol, 1.0 equiv) in CH3OH (135 mL) was stirred for 2 h at room temperature. The mixture was acidified to pH 4 with 10% HC1 (70 mL) and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (10-50%), to afford the title compound (10.8 g).

Step 5: 1 -(tert-butyl) 2-m ethyl (5S)-2-(2-(chloromethyl)allyl)-5- (methoxymethyl)pyrrolidine-l,2-dicarboxylate

Boc

To a solution of 1 -(tert-butyl) 2-methyl (5S)-5-(methoxymethyl)pyrrolidine-l,2- dicarboxylate (10.8 g, 39.5 mmol, 1.0 equiv) in THF (108 mL) was added LiHMDS (13.2 g, 79.0 mmol, 2.0 equiv) dropwise for 30 min at -80 °C under nitrogen atmosphere, followed by addition of 3-chloro-2-(chloromethyl)prop-l-ene (19.8 g, 158.0 mmol, 4.0 equiv) dropwise. The resulting mixture was stirred for additional 12 h at room temperature and then quenched with water at 0 °C. The resulting mixture was extracted with EA and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-25%), to afford the title compound (11.3 g).

Step 6: methyl (5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-lH-pyrrolizine- 7a(5H)-carboxylate and methyl (5S,7aR)-5-(methoxymethyl)-2-methylenetetrahydro-lH- pyrrolizine-7a(5H)-carboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (5S)-2-(2-(chloromethyl)allyl)-5- (methoxymethyl)pyrrolidine-l,2-dicarboxylate (11.3 g, 31.2 mmol, 1.0 equiv) in DCM (113 mL) was added TFA (40 mL) dropwise at 5 °C. The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure. To the resulting residue was added K2CO3 (8.6 g, 62.4 mmol, 2.0 equiv.) and CH3OH (113 mL) and the mixture was stirred for 2 h at room temperature. EtOAc was added and the mixture was washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (30-50%), to afford the title compounds (4.5 g) and (400 mg). MS (ES, m/z . [M+H]⁺=226.2.

Step 7: ((5 S, 7aS)-5-(methoxymethyl)-2 -methyl enetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol and ((5 S,7aR)-5-(methoxymethyl)-2-methylenetetrahydro- IH-pyrrolizin- 7a(5H)-yl)methanol

The title compounds were prepared by proceeding analogously as described in Intermediate 2, Step 5, by reducing the ester group with Li AIH4. MS (ES, m/z): [M+H]⁺=198.2

Intermediate 25

Synthesis of ((5R,7aR)-5-(methoxymethyl)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)-m ethanol and ((5R,7aS)-5-(methoxymethyl)-2-methylenetetrahydro- IH-pyrrolizin- 7a(5H)-yl)-methanol

The title compounds were prepared by proceeding analogously as described in Intermediate 24, Steps 1-7, using 1 -(tert-butyl) 2-methyl (R)-5-oxopyrrolidine-l,2- dicarboxylate instead of 1 -(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-l,2-di carboxylate in Step 1. MS (ES, m/z): [M+H]⁺ =198.2.

Intermediate 26

Synthesis of [(2S,7aR)-2-(methoxymethyl)-6-methylidene-tetrahydro-lH-pyrrolizin-7a- yl]-methanol and ((2S,7aS)-2-(methoxymethyl)-6-methylenetetrahydro-lH-pyrrolizin- 7a(5H)-yl)-methanol

Step 1 : 1 -(tert-butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-

(methoxymethyl)pyrrolidine-l,2-dicarboxylate and 1 -(tert-butyl) 2-methyl (2S,4S)-2-(2-

(chloromethyl)allyl)-4-(methoxy-methyl)pyrrolidine-l,2-dicarboxylate

To a stirred solution of HMDS (12.2 g, 75.6 mmol, 1.15 equiv) in THF (360 mL) was added n-BuLi (30.3 mL, 75.6 mmol, 1.15 equiv., 2 .5 M in hexane) dropwise at -78 °C under nitrogen atmosphere and the resulting mixture was stirred for 30 min. 1 -tert-butyl 2- Methyl (2S,4S)-4-(methoxymethyl)pyrrolidine-l,2-dicarboxylate (18 g, 65.9 mmol, 1 equiv) was added dropwise at -78 °C and the resulting mixture was stirred for 15 min. 3- Chloro-2-(chloromethyl)prop-l-ene (20.5 g, 164 mmol, 2.5 equiv) was added dropwise at -78 °C and the mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The mixture was quenched by the addition of saturated NH4CI (aq.) at room temperature and extracted with EA. The combined organic layers were washed with brine, and dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-10%), to afford the title compound (19.9 g).

Step 2: methyl (2S,7aR)-2-(methoxymethyl)-6-methylidene-tetrahydro-lH-pyrrolizine-7a- carboxylate [A] and methyl (2S,7aS)-2-(methoxymethyl)-6-methylidene-tetrahydro-lH- pyrrolizine-7a-carboxylate [B]

To a stirred solution of 1 -tert-butyl 2-methyl (2R,4S)-2-[2-(chloromethyl)prop-2-en-

1-yl]-4-(methoxymethyl)pyrrolidine-l,2-dicarboxylate and 1 -tert-butyl 2-methyl (2S,4S)-

2-[2-(chlorom ethyl )prop-2-en- 1 -yl] -4-(methoxymethyl)pyrrolidine- 1 ,2-dicarboxylate (10 g, 13.8 mmol, 1 equiv.) in DCM (75 mL) was added TFA (25 mL) dropwise at 5 °C and the resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under vacuum. Methanol (100 mL) and K2CO3 (19 g, 138 mmol, 10 equiv) were added to the residue, and the mixture was stirred for 2 h at room temperature. After the volatile solvents were removed under vacuum, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%). The material was further purified by prep-HPLC to afford the title compounds.

Step 4: [(2S,7aR)-2-(methoxymethyl)-6-methylidene-tetrahydro-lH-pyrrolizin-7a- yl]methanol

The title compounds were prepared by proceeding analogously as described in Intermediate 2, Step 5, by reducing methyl (2S,7aR)-2-(methoxymethyl)-6-methylidene- tetrahydro-lH-pyrrolizine-7a-carboxylate and methyl (2S,7aS)-2-(methoxymethyl)-6- methylidene-tetrahydro-lH-pyrrolizine-7a-carboxylate with LiAlEU MS (ES, m/z): [M+H]⁺= 198.2.

Intermediate 27

Synthesi s of ((5 S, 7aS)-2-methylene-5 -(3 ,3 , 3 -trifluoropropyl )tetrahydro- 1 H-pyrrolizin- 7a(5H)-yl)-methanol

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,5S)-5-hydroxy-5-(3,3,3-trifluoropropyl)pyrrolidine- 1,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl (2R)-5-oxopyrrolidine-l,2-dicarboxylate (15 g, 61.7 mmol, 1.0 eq.) in THF (150 mL) was added (3,3,3-trifluoropropyl)magnesium chloride (2.0 M in THF solution, 185 mL, 92.5 mmol, 1.5 eq.) dropwise at -40 °C under nitrogen atmosphere and the resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding sat. NH4CI aq. solution at 0 °C and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%), to afford the title compound (8 g). Step 2: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3,3,3-trifluoropropyl)pyrrolidine-l,2- dicarboxylate

To a solution of 1-tert-butyl 2-methyl (2R,5S)-5-hydroxy-5-(3,3,3-trifluoropropyl)- pyrrolidine-l,2-dicarboxylate (7 g, 20.5 mmol, 1.0 eq.) in EtOAc (70 mL) was added NaBH(OAc)3 (5.65 g, 26.7 mmol, 1.3 eq.) at 0 °C under nitrogen atmosphere and the reaction mixture was then stirred for 30 min. at 0 °C. TFA (7.7 g, 67.7 mmol, 3.3 eq.) was added dropwise at 0 °C and the resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat. NaHCOs aq. solution at 0 °C and the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%), to afford the title compound (5 g).

Step 3 : ((5S,7aS)-2-methylene-5-(3,3,3-trifluoropropyl)tetrahydro-lH-pyrrolizin-7a(5H)- yl)-methanol

The title compound was prepared by proceeding analogously as described in Intermediate 6, Steps 5-7, using 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3,3,3- trifluoropropyl)pyrrolidine-l,2-dicarboxylate instead of of (5 S)- 1-tert-butyl 2-methyl 5- (((tert-butyldiphenylsilyl)oxy)methyl)-pyrrolidine-l,2-dicarboxylate in Step 5. MS (ES, m/z): [M+H]⁺= 250.2

Intermediate 28

Synthesis of ((5S,7aS)-5-isobutyl-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 27, Steps 1-3, using isobutylmagnesium bromide instead of (3,3,3- trifluoropropyl)-magnesium chloride in Step 1. MS (ES, m/z): [M+H]⁺=210.3. Intermediate 29

Synthesis of ((5S,7aS)-5-isoproypl-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 27, Steps 1-3, using bromo(isopropyl)magnesium instead of (3,3,3-trifluoro- propyl)magnesium chloride in Step 1. MS (ES, m/z . [M+H]⁺=196.2.

Intermediate 30

Synthesis of ((2S,7aR)-2-(difluoromethoxy)-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl) methanol

Step 1 : methyl (2S,7aR)-2-(difluoromethoxy)-6-methylenetetrahydro-lH-pyrrolizine-

7 a(5H)-carboxyl ate

To a mixture of methyl (2S,7aR)-2-hydroxy-6-methylidene-tetrahydro-lH- pyrrolizine-7a-carboxylate (1.0 g, 5.1 mmol, 1.0 eq.) and Cui (386 mg, 2 mmol, 0.40 eq.) in CEECN (10 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.4 g, 30.6 mmol, 6.0 eq.) dropwise at 50 °C under nitrogen atmosphere and the resulting mixture was stirred for 1.5 h at 50 °C. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-30%). The material was further purified by reverse flash chromatography to afford the title compound (140 mg).

Step 2: ((2S,7aR)-2-(difluoromethoxy)-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl) methanol

The title compound was prepared by proceeding analogously as described in Intermediate 1, Step 2, by reducing the ester group with LiAlEL.

Intermediate 31

Synthesis of ((6R,7aS)-6-fluoro-l-methyl-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)-methanol

Step 1 : 3-((tert-butyldimethylsilyl)oxy)-2-methylenebutyl 4-methylbenzenesulfonate

To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-methylenebutan-l-ol (16 g, 74 mmol, 1 eq.) (J Org. Chem. 1996, 61, 6936 - 6940]) and TEA (22 g, 222 mmol, 3.0 eq.) in DCM (150 mL) was added -toluenesulfonyl chloride (17 g, 89 mmol, 1.2 eq.) at room temperature, and the resulting mixture was stirred overnight at room temperature. The mixture was then concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-10%), to afford the title compound (12 g)-

Step 2: methyl (2S,4R)-l-(3-((tert-butyldimethylsilyl)oxy)-2-methylenebutyl)-4- fluoropyrrolidine-2-carboxylate

To a stirred solution of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloride (3.5 g, 19.0 mmol, 1.0 eq.) and TEA (5.8 g, 57 mmol, 3.0 eq.) in DMF (100 mL) was added 3-[(tert-butyldimethylsilyl)oxy]-2-methylidenebutyl 4- methylbenzenesulfonate (7 g, 19 mmol, 1.0 eq.) dropwise at 0 °C under nitrogen atmosphere and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with diethyl ether and the organic layer washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-10%), to afford the title compound (4.7 g).

Step 3: methyl (2S,4R)-4-fluoro-l-(3-hydroxy-2-methylenebutyl)pyrrolidine-2- carboxylate

To a stirred solution of methyl (2S,4R)-l-{3-[(tert-butyldimethylsilyl)oxy]-2- methylidenebutyl}-4-fluoropyrrolidine-2-carboxylate (4.7 g, 13.6 mmol, 1.0 eq.) in THF (50 mL) was added TBAF (1.0 M solution in THF, 27.2 mL, 27.2 mmol, 2.0 eq.) at room temperature and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with THF/PE (0-30%), to afford the title compound (2.0 g)-

Step 4: methyl (2S,4R)-l-(3-chloro-2-methylenebutyl)-4-fluoropyrrolidine-2-carboxylate

A solution of methyl (2S,4R)-4-fluoro-l-(3-hydroxy-2 -methylenebutyl) pyrrolidine- 2-carboxylate (2 g, 8.6 mmol, 1 eq.) in phosphorus oxychloride (10 mL) was stirred for 30. min at 50 °C. After cooling to rt, the mixture was concentrated under reduced pressure. DCM as added and the organic layer was washed with brine, dried over anhydrous

Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-20%), to afford the title compound (240 mg).

Step 5: methyl (6R,7aS)-6-fluoro-l-methyl-2-methylenetetrahydro-lH-pyrrolizine-

7 a(5H)-carboxyl ate

To a stirred solution of methyl (2S,4R)-l-(3-chloro-2-methylenebutyl)-4-fluoro- pyrrolidine-2-carboxylate (700 mg, 2.8 mmol, 1 eq.) in THF (20 mL) were added IM LiHMDS in THF (11 mL, 11 mmol, 4 eq.) dropwise at 0 °C. The resulting mixture was stirred for 1 h at 0 °C and then diluted with water. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-30%), to afford the title compound (100 mg, 16.7%) as a yellow oil.

Step 6: ((6R,7aS)-6-fluoro-l-methyl-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 1, Step 2, by reducing the ester group with LiAlHj. [M+H]⁺=186.2.

Intermediate 32

Synthesis of ((2S,3R,7aR)-2-fluoro-3-methyl-6-methylenetetrahydro-lH-pyrrolizin-

7a(5H)-yl)methanol

* stereochemistry assignment tentative

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-2-(2-

(chloromethyl)-allyl)-5-methylpyrrolidine-l,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R,5R)-4-((tert- butyldimethylsilyl)oxy)-5-methylpyrrolidine-l,2-dicarboxylate (22.0 g, 58.8 mmol, 1 equiv.) in THF (250 mL) was dr op wise added LiHMDS (1 M, 117 mL, 2 equiv.) and the mixture was stirred at -60 °C for 1 h. 3-Chloro-2- (chloromethyl prop-l-ene (11.0 g, 88.3 mmol, 1.5 eq) was added and the resulting solution was stirred at 20 °C for 2 h. The mixture was quenched with water at 5 °C, and extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by column chromatography, eluted with (EA/PE = 0-20%), to afford the title compound (22.0 g).

Step 2: 1 -(tert-butyl) 2-methyl (2R,4R,5R)-2-(2-(chloromethyl)allyl)-4-hydroxy-5-methyl- pyrrolidine- 1 ,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R,5R)-4-((tert- butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)-5-methylpyrrolidine-l,2-dicarboxylate (21.0 g, 45.4 mmol, 1 eq) in DMF (120 mL) was added CsF (40.0 g, 263 mmol, 9.72 mL, 5.8 eq) and FEO (2.46 g, 136 mmol, 2.46 mL, 3 eq) and the mixture was stirred at 60 °C for 12 h under N2. After cooling to rt, the mixture was filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE(0-50%), to afford the title compound (14.0 g).

Step 3: 1 -(tert-butyl) 2-methyl (2R,4S,5R)-2-(2-(chloromethyl)allyl)-4-fluoro-5-methyl- pyrrolidine- 1 ,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R,5R)-2-(2-(chloromethyl)allyl)-4- hydroxy-5-methylpyrrolidine-l,2-dicarboxylate (1.00 g, 2.87 mmol, 1 eq) in DCM (20 mL) was added BAST (1.91 g, 8.62 mmol, 1.89 mL, 3 eq) at -60 °C. The mixture was slowly warmed to 20 °C and stirred at 20 °C for 12 h. The mixture was quenched with sat. NaHCOs aq. solution at 5 °C, and then extracted with dichloromethane. The combined organic layers were concentrated and the residue was purified by column chromatography, eluted with EA/PE (0-10%), to afford the title compound (1.50 g).

Step 4. ((2S,3R,7aR)-2-fluoro-3-methyl-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

* stereochemistry assignment tentative

The title compound was prepared by proceeding analogously as described in Intermediate 2, Steps 4-5 using 1 -(tert-butyl) 2-methyl (2R,4S,5R)-2-(2- (chloromethyl)allyl)-4-fluoro-5-methylpyrrolidine-l,2-dicarboxylate instead of 1 -tert- butyl 2-methyl (2R,4S)-2-[2-(chloromethyl)prop-2-en-l-yl]-4-fluoropyrrolidine-l,2- dicarboxylate in Step 4.

Intermediate 33

Synthesis of (2-ethylidenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

Step 1 : ethyl 2-ethylidene-5-oxotetrahydro-lH-pyrrolizine-7a(5H)-carboxylate

A mixture of ethyl 2-methyl ene-5 -oxotetrahydro- lH-pyrrolizine-7a(5H)- carboxylate (1.5 g, 7.2 mmol, 1.0 eq.) and Grubbs 2nd generation catalyst (0.61 g, 0.74 mmol, 0.1 eq.) in DCM (10 mL) was stirred for 12 h at room temperature under propylene atmosphere. The resulting mixture was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (35%), to afford the title compound (500 mg, 30.6%) as a light-yellow oil.

Step 2: (2-ethylidenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 1, Step 2 by reducing the ester with Li AIH4. MS (ES, m/z): [M+H]⁺= 168.2.

Intermediate 34

Synthesis of (2-(2-methoxyethylidene)tetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 33, using 3 -methoxyprop- 1-ene (5.0 eq.) instead of propylene in Step 1.

Intermediate 35

Synthesis of (2-butylidenetetrahydro- lH-pyrrolizin-7a(5H)-yl)m ethanol

The title compound was prepared by proceeding analogously as described in Intermediate 33, using, using pent-l-ene (5.0 eq.) instead of propylene in Step 1.

Intermediate 36

Synthesis of (2-(2-methylpropylidene)tetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 33, using 3 -methyl- 1 -butene (5.0 eq.) instead of propylene in Step 1. MS (ES, m/z): [M+l]⁺ =196.1.

Intermediate 37

Synthesi s of (2-(3 -methylbutylidene)tetrahydro- 1 H-pyrrolizin-7 a(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 33, using 3 -methyl- 1 -pentene (5.0 eq.) instead of propylene in Step 1. MS (ES, m/z . [M+l]⁺ =196.1

Intermediate 38

Synthesis of ((2R,3R,7aR)-2-fluoro-3-methyl-6-methylenetetrahydro-lH-pyrrolizin- 7a(5H)-yl)methanol

* stereochemistry assignment tentative

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,4S,5R)-2-(2-(chloromethyl)allyl)-5-methyl-4-((4- nitrobenzoyl)oxy)pyrrolidine-l,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,4R,5R)-2-(2-(chloromethyl)allyl)-4- hydroxy-5-methylpyrrolidine-l,2-dicarboxylate (6.00 g, 17.2 mmol, 1 eq), 4-nitrobenzoic acid (3.17 g, 18.9 mmol, 1.1 eq) and PPhs (6.79 g, 25.8 mmol, 1.5 eq) in THF (60 mL) was added DIAD (5.23 g, 25.8 mmol, 5.03 mL, 1.5 eq) at 0 °C and the mixture was stirred at 20 °C for 12 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by column chromatography, eluted with EA/PE (0-20%) to afford the title compound (5.00 g) as a yellow oil.

Step 2: methyl (2S,3R,8R)-3-methyl-6-methylene-2-(4-nitrobenzoyl)oxy-2, 3,5,7- tetrahydro-lH-pyrrolizine-8-carboxylate

To a solution of 1-tert-butyl 2-methyl (2R,4S,5R)-2-[2-(chloromethyl)allyl]-5- methyl-4-(4-nitrobenzoyl)oxy-pyrrolidine-l,2-dicarboxylate (1.00 g, 2.01 mmol, 1 eq) in DCM (12 mL) was added TFA (6.16 g, 54.0 mmol, 4 mL, 26.8 eq) and the mixture was stirred at 20 °C for 2 h. The mixture was concentrated and the residue was dissolved in THF. K2CO3 (834 mg, 6.04 mmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 2 h. The mixture was then filtered and concentrated to afford the title compound (2.9 g, crude).

Step 3: methyl (2S,3R,8R)-2-hydroxy-3-methyl-6-methylene-2,3,5,7-tetrahydro-lH- pyrrolizine-8-carboxylate

To a solution of methyl (2S,3R,8R)-3-methyl-6-methylene-2-(4-nitrobenzoyl)oxy- 2,3,5,7-tetrahydro-lH-pyrrolizine-8-carboxylate (2.90 g, 8.05 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (2.78 g, 20.1 mmol, 2.5 eq) and the mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-50%) to afford the title compound (700 mg).

Step 4. methyl (2R,3R,8R)-2-fluoro-3-methyl-6-methylene-2,3,5,7-tetrahydro-lH- pyrrolizine-8-carboxylate

To a solution of methyl (2S,3R,8R)-2-hydroxy-3-methyl-6-methylene-2, 3,5,7- tetrahydro-lH-pyrrolizine-8-carboxylate (0.25 g, 1.18 mmol, 1 eq) in DCM (4 mL) was added DAST (572 mg, 3.55 mmol, 469 uL, 3 eq) dropwise at -60 °C. The mixture was warmed to rt and stirred for 12 h. The reaction mixture was cooled in ice water bath and quenched with water. The mixture was extracted with EtOAc and the combined organic layers were concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-30%), to afford the title compound (170 mg).

Step 5: ((2R,3R,7aR)-2-fluoro-3-methyl-6-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

* stereochemistry assignment tentative

The title compound was prepared by proceeding analogously as described in Intermediate 2, Step 5, by reducing the ester group with LiAlEU. MS (ES, m/z): [M+H]⁺=186.2.

Intermediate 39

Synthesis of (l-methyl-l,5,6,8-tetrahydropyrazolo[4,3-a]pyrrolizin-3b(4H)-yl)methanol

Step 1 : 1 -(tert-butyl) 2-m ethyl (S,E)-3-((dimethylamino)methylene)-4-oxopyrrolidine-l,2- dicarboxylate

A solution of 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-l,2-dicarboxylate (20.0 g, 82.2 mmol, 1.0 eq.) and DMF-DMA (13.9 g, 116.6 mmol, 1.4 eq.) in DMF (100 mL) was stirred overnight at 105 °C. The reaction mixture was cooled and then diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (50%), to afford the title compound (13.2 g, 53.8%) as a brown oil. Step 2: 5 -(tert-butyl) 4-methyl (S)-2,6-dihydropyrrolo[3,4-c]pyrazole-4,5(4H)- dicarboxylate

Boc

To a stirred solution of 1 -(tert-butyl) 2-methyl (S,E)-3- ((dimethylamino)methylene)-4-oxopyrrolidine-l,2-di carboxylate (13.2 g, 44.2 mmol, 1.0 eq.) in EtOH (60 mL) was added 80% NH2NH2 H2O (3.2 g, 63.9 mmol, 1.4 eq.) dropwise at room temperature. The resulting mixture was stirred for 3 h at room temperature, diluted with water and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was dissolved in DCM (100 mL) and then a solution of TsOH (2.0 g, 11.6 mmol, 0.26 eq.) in MeOH (20 mL) was added dropwise at 0-5 °C. The resulting mixture was stirred for 2 h at 0-5 °C, diluted with water, and then extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (50%), to afford the title compound (6.0 g, 50.7%) as a yellow oil.

Step 3: 5 -(tert-butyl) 4-methyl (S)-l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(lH)- dicarboxylate

To a stirred mixture of 5 -(tert-butyl) 4-methyl (S)-2,6-dihydropyrrolo[3,4- c]pyrazole-4,5(4H)-di carboxylate (6.0 g, 22.4 mmol, 1.0 eq.) and K2CO3 (4.6 g, 33.3 mmol, 1.5 eq.) in DMF (3 mL) was added CH3I (9.6 g, 67.6 mmol, 3.0 eq.) dropwise at 0 °C. After stirring at ambient temperature overnight, the reaction mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous TsfeSCU, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-70%), to afford the title compound (5.5 g, 87.5%) as a yellow solid..

Step 4: 1 -(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2- (chloromethyl)allyl)-pyrrolidine- 1 ,2-dicarboxylate

To a stirred solution of HMDS (988 mg, 6.1 mmol, 1.1 eq.) in THF (20 mL) was added 2.5 M n-BuLi in n-hexane (2.4 mL, 6.0 mmol, 1.1 eq.) slowly at -78 °C under nitrogen atmosphere. After stirring for 30 min, a solution of 5 -(tert-butyl) 4-methyl (S)-l- methyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-4,5(lH)-dicarboxylate (1.55 g, 5.5 mmol, 1.00 eq.) in THF (20 mL) was added slowly at -78 °C. The resulting mixture was stirred for 15 min at -78 °C, and then l-bromo-3 -chloropropane (1.04 g, 6.6 mmol, 1.2 eq.) was added dropwise. The resulting mixture was stirred for additional 12 h at ambient temperature, quenched with NH4CI aq. at 5 °C and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (30%), to afford the title compound (1.0 g, 50.9%) as a light yellow oil. Step 5: (l-methyl-l,5,6,8-tetrahydropyrazolo[4,3-a]pyrrolizin-3b(4H)-yl)methanol

A solution of 5 -(tert-butyl) 4-methyl 4-(3 -chloropropyl)- l-methyl-4, 6- dihydropyrrolo [3,4-c]pyrazole-4,5(lH)-dicarboxylate (1.2 g, 3.4 mmol, 1.0 eq.) and TFA (1.0 mL) in THF (10 mL) was stirred at 0 °C for 1 h. The resulting mixture was concentrated. The residue was dissolved in MeOH (10 mL) and then K2CO3 (10.0 g, 72.4 mmol, 21.3 eq.) was added at 25 °C. The resulting mixture was stirred for additional 1 h at 25 °C and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (50%), to afford the title compound (300 mg, 41.2%) as a light- yellow oil.

Step 6: (l-methyl-l,5,6,8-tetrahydropyrazolo[4,3-a]pyrrolizin-3b(4H)-yl)methanol

The title compound was prepared by proceeding analogously as described in

Intermediate 1, Step 2. MS (ES, m/z): [M+H]⁺ = 194.2. Intermediate 40

Synthesis of (7-methylenehexahydroindolizin-8a(lH)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 14, Steps 2-6, using 1 -(tert-butyl) 2-methyl 4-methylenepiperi dine- 1,2- dicarboxylate instead of 1 -(tert-butyl) 2-ethyl indoline- 1,2-dicarboxylate in Step 2.

Intermediate 41

Synthesis of (2-methylenehexahydroindolizin-8a(lH)-yl)methanol

Step 1 : methyl l-(2-(chloromethyl)allyl)piperidine-2-carboxylate

To a stirred mixture of methyl piperidine-2-carboxylate (0.6 g, 4.2 mmol, 1.0 eq.) and K2CO3 (848 mg, 6.1 mmol, 1.5 eq.) in DMF (5 mL) was added 3-chloro-2- (chloromethyl)prop-l-ene (756 mg, 6.0 mmol, 1.4 eq.) at 0 °C. The result mixture was stirred for 16 h at room temperature, quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and then concentrated to afford the title compound as a yellow oil (1.0 g, crude, 100%), which was used for next step without further purification.

Step 2: methyl 2-methylenehexahydroindolizine-8a(lH)-carboxylate

To a stirred solution of methyl l-(2-(chloromethyl)allyl)piperidine-2-carboxylate (1.0 g, 4.3 mmol, 1.0 eq.) in anhydrous THF (10 mL) was added 1.0 M LiHMDS (8.0 mL, 8.0 mmol, 1.9 eq.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 2 h, and then at room temperature for 16 h. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purification by silica gel chromatogram;y, eluting with EA/PE (0-50%), to afford the title compound (0.60 g, 72.1%) as a yellow oil.

Step 3: (2-methylenehexahydroindolizin-8a(lH)-yl)methanol

The title compound was prepared by proceeding analogously as described in the synthesis of Intermediate 1, Step 2.

Intermediate 42

Synthesis of 2,2,2-trifhioro-l-((lS,5R)-2-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-

1-one

Step 1 : tert-butyl (lS,5R)-8-benzyl-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Boc Boc

To a stirred solution of tert-butyl (lR,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate (1.1 g, 3.6 mmol, 1.0 eq.) and TMEDA (2.2 g, 18.9 mmol, 5.2 eq.) in THF (5 mL) was added 1.3M s-BuLi in n-hexane (14.5 mL, 18.9 mmol, 5.3 eq.) at -78 °C. The resulting mixture was stirred for 1 h at -78 °C, and then Mel (1.0 g, 7.0 mmol, 1.9 eq.) was added dropwise. The resulting mixture was stirred for 2 h at room temperature, quenched with water and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous ISfeSCU, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (0-10%), to afford the title compound (880 mg, 77.8%) as a light yellow oil.

Step 2: tert-butyl (lS,5R)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

i i Boc Boc

A mixture of tert-butyl (lS,5R)-8-benzyl-2-methyl-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (1.1 g, 3.5 mmol, 1.0 eq.) and 5% Pd/C (185 mg) in MeOH (10 mL) was stirred under hydrogen atmosphere at room temperature for 16 h. The reaction mixture was filtered through a Celite pad and then concentrated to afford the title compound (760 mg, 97.1%) as a light- yellow oil.

Step 3: tert-butyl (lS,5R)-2-methyl-8-(2,2,2-trifluoroacetyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate

Boc

To a stirred solution of tert-butyl (lS,5R)-2-methyl-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate (880 mg, 3.9 mmol, 1.0 eq.) and TEA (1.18 g, 11.7 mmol, 3.0 eq.) in DCM (10 mL) was added TFAA (2.5 g, 11.9 mmol, 3.1 eq.) at 0 °C under nitrogen atmosphere. After stirring for 1 h, the reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE/THF (0-20%), to afford the title compound (560 mg, 43.6%) as a light- yellow oil.

Step 4: 2,2,2-trifluoro-l-((lS,5R)-2-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-l-one

To a stirred solution of tert-butyl (lS,5R)-2-methyl-8-(2,2,2-trifluoroacetyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (500 mg, 1.55 mmol, 1.00 eq.) in DCM (5 mL) was added HC1 in 1,4-dioxane (2.5 mL, 4.0 M) at 0 °C. The resulting mixture was stirred at room temperature for 1 h, concentrated, diluted with ACN, and then basified to pH = 7 with K2CO3 (powder). The resulting mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated to give the title compound (210 mg, 61.3%) as a light -yellow oil. MS (ES, m/z [M+H]⁺ =223.1.

Intermediate 43

Synthesis of 3,8-diazabicyclo[3.2. l]oct-6-ene-6-carbonitrile bis(2,2,2-trifluoroacetate)

Step 1 : tert-butyl 3-bromo-9-(2-phenylpropan-2-yl)-3a,4,5,7,8,8a-hexahydro-6H-4,8- epiminoisoxazolo[4,5-d]azepine-6-carboxylate

A mixture of tert-butyl (lR,5S)-8-(2-phenylpropan-2-yl)-3,8- diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (1.00 g, 3.04 mmol, 1.00 eq.), hydroxycarbonimidic dibromide (1.24 g, 6.11 mmol, 2.00 eq.) and NaHCOs (1.28 g, 15.24 mmol, 5.01 eq.) in EtOAc (10 mL) was stirred for 16 h at 75

°C under nitrogen atmosphere. The reaction mixture was cooled, quenched with water, and then extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (12: 1), to afford the title compound (0.95 g, 69.4%) as a white soild.

Step 2: tert-butyl 6-cyano-7-hydroxy-8-(2-phenylpropan-2-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate

A mixture of tert-butyl (3aR,4S,8S,8aR)-3-bromo-9-(2-phenylpropan-2-yl)- 3a,4,5,7,8,8a-hexahydro-6H-4,8-epiminoisoxazolo[4,5-d]azepine-6-carboxylate (900 mg, 2.00 mmol, 1.00 eq.), boric acid (371 mg, 6.00 mmol, 3.00 eq.) and Raney Ni (8.56 mg) in MeOH (5 mL) and FLO (1 mL) was stirred for 2 h at RT under hydrogen atmosphere (2 atm). The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (380 mg, 51.0%) as an off-white oil.

Step 3: tert-butyl 6-cyano-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3- carboxylate

To a stirred solution of tert-butyl (lS,5S,7R)-6-cyano-7-hydroxy-8-(2- phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (380 mg, 1.02 mmol, 1.00 eq.) and TEA (207.02 mg, 2.05 mmol, 2.00 eq.) in DCM (10 mL) was added MsCl (140.61 mg, 1.23 mmol, 1.20 eq.) dropwise at 0 °C under nitrogen atmosphere. After stirring at RT for 16 h, the reaction mixture was quenched with water and then extracted with DCM. The combined organic layers were concentrated. The residue was dissolved in DCE (10 mL), and to the resulting solution was added DBU (467.18 mg, 3.07 mmol, 3.00 eq.) dropwise at RT. After stirring further at RT for Ih, the reaction mixture was quenched with water and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10: 1) to afford the title compound (295 mg, 81.4%) as a white solid.

Step 4: 3,8-diazabicyclo[3.2.1]oct-6-ene-6-carbonitrile bis(2,2,2-trifluoroacetate)

A mixture of tert-butyl (lR,5S)-6-cyano-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo [3.2.1]oct-6-ene-3-carboxylate (290 mg, 0.82 mmol, 1.00 eq.) in TFA (3 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction mixture was cooled and then concentrated. The residue was triturated with Et2O to afford the title compound (215 mg, 72.0%) as a white oil.

Intermediate 44

Synthesis of (lR,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene bis(2,2,2-trifluoroacetate)

Step 1 : tert-butyl (3 S,4R)-3,4-dihydroxypyrrolidine-l -carboxylate

To a stirred solution of tert-butyl 2,5-dihydro-lH-pyrrole-l-carboxylate (2.5 g, 14.78 mmol, 1.00 eq.) in acetone (24 mL) and H2O (6 mL) was added NMO (2.6 g, 22.16 mmol, 1.50 eq.) and K2OSO4 2H2O (163 mg, 0.44 mmol, 0.030 eq.) in portions at RT under nitrogen atmosphere. The resulting mixture was stirred for 3 h at RT, quenched with aqueous NaiSiCh and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with DCMZEA (10: 1 to 1 : 10), to afford the title compound (2.8 g, 93.2%) as a yellow oil.

Step 2: tert-butyl bis(2-hydroxybut-3-en-l-yl)carbamate

To stirred solution tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-l-carboxylate (2.50 g, 12.30 mmol, 1.00 eq.) in DCM (25 mL) was added (diacetoxyiodo)benzene (5.94 g, 18.44 mmol, 1.50 eq.) slowly at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at RT, cooled to -78 °C and then added 1.0 M vinylmagnesium bromide in THF (74 mL, 74.0 mmol, 6.02 eq.) slowly over 20 minutes. After stirring forl6 h at RT, the reaction mixture was quenched with 1.0 M aqueous HC1 and then extract with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (1/1), to afford the title compound (2.6 g, 82.1%) as a yellow oil. Step 3: ((tert-butoxycarbonyl)azanediyl)bis(but-3-ene-l,2-diyl) bis(2,2,2- tri chi oroacetimi date)

To a stirred solution of tert-butyl bis(2-hydroxybut-3-en-l-yl)carbamate (1.2 g, 4.66 mmol, 1.00 eq.) in DCM (16 mL) were add 2, 2, 2-tri chloroacetonitrile (4.04 g, 27.98 mmol, 6.00 eq.), DBU (0.35 g, 2.30 mmol, 0.49 eq.) dropwise at 0 °C. After stirring for 18h at RT, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1), to afford title compound (0.8 g, 31.3%) as a yellow oil.

Step 4: tert-butyl (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-l-carboxylate

To a stirred solution of 2-phenylpropan-2-amine (238 mg, 1.76 mmol, 1.21 eq.) in DCE (5 mL) was added [Ir(cod)Cl]2 (49 mg, 0.074 mmol, 0.051 eq.), followed by a solution of ((tert-butoxycarbonyl)azanediyl)bis(but-3-ene-l,2-diyl) bis(2,2,2- trichloroacetimidate) (800 mg, 1.46 mmol, 1.00 eq.) in DCE (4.4 mL) dropwise at 0 °C under nitrogen atmosphere. After stirring overnight at RT, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with PEZEA (5: 1), to afford the title compound (315 mg, 60.3%) as a yellow oil. Step 5: (lR,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate

To a stirred solution of tert-butyl (3S,5R)-4-(2-phenylpropan-2-yl)-3,5- divinylpiperazine-1 -carboxylate (315 mg, 0.88 mmol, 1.00 eq.) in toluene (10 mL) was added Grubbs 2nd generation catalyst (37.51 mg, 0.044 mmol, 0.050 eq.) in one portion at RT under nitrogen atmosphere. The reaction mixture was stirred for 12 h at 120 °C, cooled and then concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1), to afford the title compound (70 mg, 23.9%) as a light-yellow oil. Step 6: (lR,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene bis(2,2,2-trifluoroacetate)

A mixture of tert-butyl (lR,5S)-8-(2-phenylpropan-2-yl)-3,8- diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (200 mg, 0.61 mmol, 1.00 eq.) in TFA (3 mL) was refluxed for 2 h under nitrogen atmosphere. The reaction mixture was concentrated and the residue was triturated with Et2O to afford the title compound (172.3 mg, 83.6%) as a white oil.

Intermediate 45

Synthesis of 6-methylene-3,8-diazabicyclo[3.2.1]octane bis(2,2,2-trifluoroacetate)

Step 1 : tert-butyl 6-hydroxy-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate

To a stirred solution of tert-butyl 8-(2-phenylpropan-2-yl)-3,8- diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (374 mg, 1.14 mmol, 1.00 eq.) in THF (12 mL) was added 1.0 M BH3 THF (4.5 mL, 4.5 mmol, 3.95 eq.) dropwise at 0 °C under nitrogen atmosphere. After stirring overnight at RT, 5% NaOH (aq.) (4.5 mL) was added over 10 min, followed by 30% H2O2 (390 mg, 3.44 mmol, 3.02 eq.) at 0 °C. The resulting mixture was stirred for Ih at RT and then extracted with DCM. The organic layer was concentrated and the residue was purified by trituration with Et2O to afford he title compound (300 mg, 76.3%) as a white oil.

Step 2: tert-butyl 6-oxo-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate

To a stirred solution of tert-butyl 6-hydroxy-8-(2-phenylpropan-2-yl)-3,8- diazabicyclo[3.2.1] octane-3 -carboxylate (300 mg, 0.87 mmol, 1.00 eq.) in DCM (10 mL) was added Dess-Martin reagent (551 mg, 1.30 mmol, 1.49 eq.) in portions at 0 °C. After stirring at 0 °C for Ih, the reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with water, NaHCOs (aq.), dried over Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10: 1), to afford the title compound (210 mg, 70.1%) as a yellow oil.

Step 3: tert-butyl 6-methylene-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate

A solution of methyltriphenylphosphanium iodide (528 mg, 1.31 mmol, 3.00 eq.) and t-BuOK (147 mg, 1.31 mmol, 3.00 eq.) in DMSO (3 mL) was stirred for 10 min at 10 °C under nitrogen atmosphere. To this stirred mixture was added a solution of tertbutyl (lR,5R)-6-oxo-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (150 mg, 0.44 mmol, 1.00 eq.) in DMSO (1 mL) dropwise at 10 °C. After stirring at RT for 3 h, the reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (10: 1), to afford the title compound (99 mg, 65.9%) as a yellow oil. Step 4: 6-methylene-3,8-diazabicyclo[3.2.1]octane bis(2,2,2-trifluoroacetate)

Proceeding analogously as described in Intermediate 44, Step 5, but using tertbutyl 6-methylene-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and TFA provided the title compound. Intermediate 46

Synthesis of methyl (5S,7aS)-5-(hydroxymethyl)-2-methylenetetrahydro-lH-pyrrolizine-

7a(5H)-carboxylate

Step 1 : tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methoxypyrrolidine-l- carboxylate

To a stirred solution of tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-l- carboxylate (50.0 g, 216 mmol, 1.0 eq.) and imidazole (22.0 g, 324 mmol, 1.5 eq.) in DCM (500 mL) was added TBSC1 (39.0 g, 259 mmol, 1.2 eq.) in portions at 0 °C under nitrogen atmosphere and the resulting mixture was stirred for 3 h at room temperature. After adding water, and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PEZEA (0-15%), to afford the title compound (61.0 g).

Step 2: tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-cyanopyrrolidine-l- carboxylate 1

i

Boc ^0TBS Boc OTBS

To a stirred solution of tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- m ethoxypyrrolidine- 1 -carboxylate (65.0 g, 188 mmol, 1.00 eq.) in DCM (650 mL) were added TMSOTf (2.0 g, 9.4 mmol, 0.05 eq.) and TMSCN (28.0 g, 282 mmol, 1.50 eq.) dropwise at -78 °C under nitrogen atmosphere and the resulting mixture was stirred for 1 h at -78 °C. The mixture was quenched with sat. NaHCOs (aq.) at -78 °C and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (32.0 g)- Step 3: 1 -(tert-butyl) 2-methyl (5S)-5-(hydroxymethyl)pyrrolidine-l,2-dicarboxylate

A mixture of tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- cyanopyrrolidine-1 -carboxylate (32.0 g, 94 mmol, 1.00 eq.) and K2CO3 (26.0 g, 188 mmol, 2.00 eq.) in MeOH (340 mL) was stirred for 3 h at room temperature. The mixture was acidified to pH = 2 with 10% HC1 aq. solution and the resulting mixture was stirred for 16 h at room temperature. The mixture was then extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (17.0 g).

Step 4: 1 -(tert-butyl) 2-methyl (5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine- 1,2-dicarboxylate

O. Boc Boc

To a stirred solution of 1 -(tert-butyl) 2-methyl (5S)-5-(hydroxymethyl)pyrrolidine- 1,2-dicarboxylate (17.0 g, 65.5 mmol, 1.00 eq.) and imidazole (6.69 g, 98.3 mmol, 1.50 eq.) in DCM (170 mL) was added TBDPSC1 (21.62 g, 78.6 mmol, 1.20 eq.) dropwise at 0 °C under nitrogen atmosphere and the resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water at 0 °C and the resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%), to afford the title compound (24.0 g). Step 5: 1 -(tert-butyl) 2-methyl (2S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(2- (chlorom ethyl) allyl )pyrrolidine- 1 ,2-dicarboxylate

To a stirred solution of 1 -(tert-butyl) 2-methyl (5S)-5-(((tert-butyldiphenylsilyl)- oxy)m ethyl )pyrrolidine-l,2-dicarboxylate (23.0 g, 46.2 mmol, 1.00 eq.) in THF (230 mL) was added LiHMDS in THF (92.42 mL, 1.0 M, 92.4 mmol, 2.00 eq.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at -78 °C and then 3-chloro-2-(chloromethyl)prop-l-ene (11.55 g, 92.4 mmol, 2.00 eq.) was added dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The mixture was quenched with water at 0 °C and the resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous TsfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-10%), to afford the title compound (21.0 g).

Step 6: methyl (5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylenetetrahydro- lH-pyrrolizine-7a(5H)-carboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2S,5S)-5-(((tert-butyldiphenylsilyl)oxy) methyl)-2-(2-(chloromethyl)allyl)pyrrolidine-l,2-dicarboxylate (21.0 g, 35.82 mmol, 1.00 eq) in DCM (210 mL) was added TFA (100 mL) dropwise at room temperature and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (210 mL) and K2CO3 was added. The mixture was stirred for 40 min. at room temperature and then quenched with water at room temperature. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous TsfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-15%), to afford the title compound (8.5 g).

Step 7: methyl (5S,7aS)-5-(hydroxymethyl)-2-methylenetetrahydro-lH-pyrrolizine- 7 a(5H)-carboxyl ate

To a stirred solution of methyl (5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2-methylenetetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (8.5 g, 18.9 mmol, 1.00 eq.) in THF (85 mL) was added TBAF in THF (28.3 mL, 1 M, 28.3 mmol, 1.50 eq.) dropwise at room temperature. The resulting mixture was stirred for 3 h at room temperature and then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%), to afford the title compound (2.8 g).

Intermediate 47

Synthesis of ((5S,7aS)-5-(fluoromethyl)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)- methanol

Step 1 : methyl (5S,7aS)-5-(fluoromethyl)-2-methylenetetrahydro-lH-pyrrolizine-7a(5H)- carboxylate

To a stirred solution of methyl (5S,7aS)-5-(hydroxymethyl)-2- methylenetetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (100 mg, 0.51 mmol, 1.00 eq.) in DCM (1 m ) was added BAST (160 mg, 7.12 mmol, 1.50 eq.) dropwise at -78 °C under nitrogen atmosphere and the resulting mixture was stirred for 12 h at room temperature. After cooling to 0 °C, the reaction was quenched with brine. The resulting mixture was diluted with NaHCOs (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous TsfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-70%), to afford the title compound (30 mg).

Step 2: ((5S,7aS)-5-(fluoromethyl)-2 -methyl enetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 2, Step 5, by reducing the ester group with LiAlEU.

Intermediate 48

Synthesis of ((5S,7aS)-5-(2-fluoroethyl)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)- methanol

Step 1 : 1 -(tert-butyl) 2-m ethyl (2R,5S)-5-(2-oxoethyl)pyrrolidine-l,2-dicarboxylate

O Boc o Boo

To a solution of 1-tert-butyl 2-methyl (2R,5S)-5-(prop-2-en-l-yl)pyrrolidine-l,2- dicarboxylate (7 g, 25.989 mmol, 1.0 eq.) (prepared by the method described in Synlett 1999, 1660-1662) in THF (90 mL) and H₂O (30 mL) were added K₂OsO₄.2H₂O (0.96 g, 2.6mmol, 0.1 eq.) and NaIO₄ (16.68 g, 78.0 mmol, 3.0 eq.) at 0 °C. The resulting mixture was then stirred for 16 h at room temperature under air. The reaction mixture was filtered, the filter cake was washed with EtOAc. The filtrate was extracted with EtOAc and the combined organic layers were washed with NaElSCh (aq.) and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%), to afford the title compound (3.3 g). MS (ES, m/z): [M- 100+H]⁺=172.2.

Step 2: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-hydroxyethyl)pyrrolidine-l,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-oxoethyl)pyrrolidine-l,2- dicarboxylate (2 g, 7.8 mmol, 1 eq.) in MeOH (15 mL) was added NaBH₄ (557 mg, 14.75 mmol, 2.0 eq. in portions at 0 °C and the resulting mixture was stirred for 30 min. at 0 °C. The mixture was quenched with HC1 aq. solution to pH = 7. The mixture was concentrated under reduced pressure and the remaining material was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%), to afford the title compound (1.7 g).

Step 3: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-((methylsulfonyl)oxy)ethyl)pyrrolidine-l,2- dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-hydroxyethyl)pyrrolidine-l,2- dicarboxylate (1.4 g, 5.1 mmol, 1.0 eq.), DABCO (115 mg, 1.0 mmol, 0.2 eq.) and TEA (622 mg, 6.1 mmol, 1.2 eq.) in toluene (20 mL) was added a solution of MsCl (645 mg, 5.6 mmol, 1.1 eq.) in toluene (1 mL) at 0 °C under nitrogen atmosphere, and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/EA (0-50%), to afford the title compound (1-5 g).

Step 4: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2-fluoroethyl)pyrrolidine-l,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl (2R,5S)-5-[2-(methanesulfonyloxy)ethyl]- pyrrolidine-l,2-dicarboxylate (1.4 g, 4.0 mmol, 1 eq.) and TEA (565 mg, 5.6 mmol, 1.4 eq.) in THF (14 mL) was added TBAF (5.18 mL, 5.179 mmol, 1.3 eq.) at room temperature and the resulting mixture was stirred for 3 h at 60 °C. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous ISfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%), to afford the title compound (710 mg).

Step 5: ((5S,7aS)-5-(2-fluoroethyl)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 24, Steps 5-7 using 1 -(tert-butyl) 2-methyl (2R,5S)-5-(2- fluoroethyl)pyrrolidine-l,2-dicarboxylate instead of 1 -(tert-butyl) 2-methyl (5S)-5- (methoxymethyl)pyrrolidine-l,2-dicarboxylate in Step 4. MS (ES, m/z): [M+H]⁺=200.2.

Intermediate 49

Synthesis of ((5S,7aS)-5-(3,3-difluoropropyl)-2-methylenetetrahydro-lH-pyrrolizin- 7a(5H)-yl)methanol

Step 1 : 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3-hydroxypropyl)pyrrolidine-l,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,5S)-5-allylpyrrolidine-l,2- dicarboxylate (6.5 g, 24.1 mmol, 1.0 eq.) in THF (65 mL) was added 9-BBN (1.0 M solution in THF, 72.4 mL, 72.4 mmol, 3.0 eq.) dropwise at room temperature and the mixture was stirred overnight at room temperature. To the above mixture H2O2(30% aq. solution) (65 mL) was added, followed by sodium tetraborate decahydrate (27.6 g, 72.4 mmol, 3.0 eq.) in portions and the mixture was stirred for 3 h at room temperature. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous TsfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0- 50%), to afford the title compound (4.6 g).

Step 2: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3-oxopropyl)pyrrolidine-l,2-dicarboxylate

A solution of oxalyl chloride (2.12 g, 16.7 mmol, 2 equiv) in DCM (25 mL) was added DMSO (27 mL). After stirring for 5 min at -78°C, 1 -(tert-butyl) 2-methyl (2R,5S)- 5-(3-hydroxypropyl)pyrrolidine-l,2-dicarboxylate (2.4 g, 8.4 mmol, 1 eq.) was added dropwise at -78 °C, followed by EtsN (3.4 g, 33.4 mmol, 4 eq.). After stirring for 2 h at - 78 °C, the mixture was diluted with NH4CI aq. solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous TsfeSCU and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%), to afford the title compound (2 g).

Step 3: 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3,3-difluoropropyl)pyrrolidine-l,2- dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3-oxopropyl)pyrrolidine-l,2- dicarboxylate (2 g, 7 mmol, 1 equiv) in DCM (20 m ) was added BAST (2.33 g, 10.5 mmol, 1.5 eq.) dropwise at -10 °C and the resulting mixture was stirred for 2 h at room temperature. The mixture was diluted with water and then basified to pH = 7 with saturated NaHCOs aq. solution. The mixture was extracted with DCM, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0- 30%), to afford the title compound (350 mg).

Step 6: ((5S,7aS)-5-(3,3-difluoropropyl)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)- methanol

The title compound was prepared by proceeding analogously as described in Intermediate 24, Steps 5-7, using 1 -(tert-butyl) 2-methyl (2R,5S)-5-(3,3-difluoropropyl)- pyrrolidine-l,2-dicarboxylate instead of 1 -(tert-butyl) 2-methyl (5S)-5-(methoxymethyl)- pyrrolidine-l,2-dicarboxylate in Step 4. MS (ES, m/z): [M+H]⁺=232.1.

Intermediate 50

Synthesis of (6-fluoro-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 9, Steps 1-3, using 2-bromo-6-fluorobenzaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z): [M+H]⁺=208.1.

Intermediate 51

Synthesis of (7-fluoro-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described Intermediate 9, Steps 1-3, using 2-bromo-5 -fluorobenzaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z): [M+H]⁺= 208.1.

Intermediate 52

Synthesis of (8-fluoro-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermdiate 9, Steps 1-3, using 2-bromo-4-fluorobenzaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z): [M+H]⁺= 208.1.

Intermediate 53

Synthesis of (9-fluoro-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 9, Steps 1-3, using 2-bromo-3 -fluorobenzaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z): [M+H]⁺= 208.2.

Intermediate 54

Synthesis of (8,9-dihydro-5H-pyrido[2,3-a]pyrrolizin-9a(7H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 9, Steps 1-3, using 2-bromopyridine-3-carbaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z [M+H]⁺=191.1.

Intermediate 55

Synthesis of (6-methoxy-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described Intermediate 9, Step 1-3, using 2-bromo-6-methoxybenzaldehyde instead of 2- bromobenzaldehyde in in Step 1. MS (ES, m/z): [M+H]⁺= 220.1.

Intermediate 56

Synthesis of (7-methoxy-2,3-dihydro-lH-pyrrolo[2, l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described Intermediate 9, Stepsl-3, using 2-bromo-5-methoxybenzaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z): [M+H]⁺= 220.1

Intermediate 57

Synthesis of (6,7-dihydro-5H-pyrido[4,3-a]pyrrolizin-4b(9H)-yl)methanol

The title compound was prepared by proceeding analogously as described Intermediate 9, Stepsl-3, using 4-bromopyridine-3-carbaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z . [M+H]⁺=191.0.

Intermediate 58

Synthesis of (8,9-dihydro-5H-pyrido[3,4-a]pyrrolizin-9a(7H)-yl)methanol

The title compound was prepared by proceeding analogously as described Intermediate 9, Steps 1-3, using 3-bromopyridine-4-carbaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z)'. [M+H]⁺=191.2. Intermediate 59

Synthesis of (6-(methoxymethyl)-2,3-dihydro-lH-pyrrolo[2, l-a]isoindol-9b(5H)- yl)methanol

The title compound was prepared by proceeding analogously as described Intermediate 9, Steps 1-3, using 2-bromo-6-(methoxymethyl)benzaldehyde instead of 2- bromobenzaldehyde in Step 1. MS (ES, m/z): [M+H]⁺= 234.2.

Intermediate 60

Synthesis of: (6-(trifluoromethyl)-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)- yl)methanol

Step 1 : l-bromo-2-(bromomethyl)-3-(trifluorom ethyl )benzene

A solution of l-bromo-2-methyl-3-(trifluoromethyl)benzene (2.0 g, 8.4 mmol, 1.0 eq.) and NBS (1.8 g, 10.1 mmol, 1.2 eq.), benzoyl peroxide (0.21 g, 0.87 mmol, 0.10 eq.) in CCU (20 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was triturated in petroleum ether and the precipitated solid was collected by filtration to afford the title compound (2.0 g, 75.0%) as a yellow solid.

Step 2: tert-butyl (2-bromo-6-(trifluoromethyl)benzyl)prolinate

A mixture of l-bromo-2-(bromomethyl)-3-(trifluorom ethyl )benzene (2.0 g, 6.3 mmol, 1.0 eq.) and tert-butyl pyrrolidine-2-carboxylate (1.3 g, 7.6 mmol, 1.2 eq.) and K2CO3 (1.7 g, 12.6 mmol, 2.0 eq.) in CH3CN (20 m ) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-10%), to afford the title compound (2.1 g, 81.0%) as a yellow oil.

Step 3 : (6-(trifluoromethyl)-2,3 -dihydro- lH-pyrrolo[2, l-a]isoindol-9b(5H)-yl)methanol

The title compound was prepared by proceeding analogously as described in Intermediate 9, Steps 2-3, using tert-butyl (2-bromo-6-(trifluoromethyl)-benzyl)prolinate instead of methyl (2-bromobenzyl)prolinate in Step 2. MS (ES, m/z): [M+H]⁺ =258.1.

Intermediate 61

Synthesis of a mixture of (cis-2-fluoro-2,3-dihydro-lH-pyrrolo[2,l-a]isoindol-9b(5H)- yl)methanol and (trans-2-fluoro-2,3-dihydro-lH-pyrrolo[2, l-a]isoindol-9b(5H)- yl)methanol

The title compounds were prepared by proceeding analogously as described Intermediate 9, Step 1-3, using methyl cis-4-fluoropyrrolidine-2-carboxylate instead of methyl prolinate in Step 1. The crude product was purified by prep-HPLC to afford the title compounds (200 mg and 220 mg) as brown oil. MS (ES, m/z): [M+H]⁺= 208.2.

Example 1

Synthsis of a mixture of (3S,7aS)-7a-(((10-((R)-l-(2-aminopyridin-3-yl)ethyl)-5- (8-ethynyl-7-fluoronaphthalen- 1 -yl)-4-fluoro-9, 10-dihydro-8H-7-oxa- 1,3,6,10- tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH-pyrrolizin- 3-yl)methyl morpholine-4-carboxylate (la) and ((3S,7aS)-7a-(((10-((S)-l-(2- aminopyridin-3-yl)ethyl)-5-(8-ethynyl-7-fluoronaphthalen-l-yl)-4-fluoro-9,10-dihydro- 8H-7-oxa- 1 ,3,6, 10-tetraazacyclohepta[de] naphthal en-2-yl)oxy)methyl)-6- methylenehexahydro-lH-pyrrolizin-3-yl)methyl morpholine-4 carboxylate (lb)

Step 1 : 2-((l-(2-aminopyridin-3-yl)ethyl)amino)ethan-l-ol

To a solution of l-(2-aminopyri din-3 -yl)ethanone (4 g, 29.4 mmol, 1.0 equiv) and ethanolamine (3.6 g, 58.8 mmol, 2 equiv) in MeOH (40 mL) was added Ti(0i-Pr)4 (8.35 g,

29.4 mmol, 1.0 equiv) at 0-5°C and the resulting mixture was stirred for 3 h at 80 °C. After cooling the mixture to 0-5 °C, NaBJLCN (2.77 g, 44.067 mmol, 1.5 equiv) was added to the above mixture in portions and the resulting mixture was stirred for 16 h at 80 °C. After cooling to RT, the mixture was quenched with water, diluted with DCM and filtered. The filter cake was then washed with DCM. The phases were separated and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%) to afford the title compound (3 g).

Step 2 : 5 -(2-(( 1 -(2-aminopyri din-3 -yl)ethyl)amino)ethoxy)-7-chl oro-8 -fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-ol

To a solution of 5,7-dichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin- 4-ol (1.7 g, 6.1 mmol, 1 equiv) and 2-((l -(2-aminopyri din-3 -yl)ethyl)amino)ethan-l-ol (1.68 g, 9.3 mmol, 1.5 equiv) in THF (17 mL) was added NaH (0.73 g, 18.3 mmol, 3 equiv, 60%) in portions at and the resulting mixture was stirred for 2 h at RT. After cooling to 0-5°C, the reaction mixture was quenched with sat. NH4CI aq. solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude product was used in the next step directly without further purification.

Step 3 : 3 -( 1 -(5 -chi oro-4-fluoro-2-(m ethyl thi o)-8, 9-dihy dro- 10H-7-oxa- 1,3,6,10- tetraazacyclo-heptafde] naphthal en- 10-yl)ethyl)pyridin-2-amine

A solution of 5-(2-((l-(2-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-chloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (crude, 6.1 mmol, 1.0 equiv), bis(2-oxo- l,3-oxazolidin-3-yl)phosphinoyl chloride (3.10 g, 12.2 mmol, 2.0 equiv) and DIEA (2.36 g, 18.3 mmol, 3.0 equiv) in CHCh (100 mL) was stirred for 3 h at 70 °C . After cooling to RT, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%) to afford the title compound (700 mg).

Step 4: tert-butyl (tert-butoxycarbonyl)(3-(l-(5-chloro-4-fluoro-2-(methylthio)-8,9- dihydro- 10H-7-oxa- 1 ,3 ,6, 10-tetraazacyclohepta[de]naphthalen- 10-yl)ethyl)pyridin-2- yl)carbamate

A solution of 3-(l-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa- 1,3,6, 10-tetraazacyclohepta[de] naphthalen-10-yl)ethyl)pyridin-2-amine (700 mg, 1.72 mmol, 1.0 equiv) ,TEA (870 mg, 8.6 mmol, 5 equiv) DMAP (42 mg, 0.344 mmol, 0.2 equiv) and BOC2O (1.31 g, 6.0 mmol, 3.5 equiv) in THF (7 mL) was stirred for 40 h at RT. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-90%) to afford the title compound (670 mg).

Step 5: tert-butyl (tert-butoxycarbonyl)(3-(l-(4-fluoro-5-(7-fluoro-8-((triisopropyl- silyl)ethynyl)naphthalen- 1 -yl)-2-(methylthio)-8,9-dihydro- 10H-7-oxa- 1,3,6,10- tetraazacyclo-hepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

A mixture of tert-butyl (tert-butoxycarbonyl)(3-(l-(5-chloro-4-fluoro-2- (methylthio)-8,9-dihydro- 10H-7-oxa- 1 ,3 ,6, 10-tetraazacyclohepta[de]naphthalen- 10- yl)ethyl)pyridin-2-yl)carbamate (670 mg, 1.65 mmol, 1.0 equiv), ((2-fluoro-8-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (1.12 g, 2.47 mmol, 1.5 equiv), CataCXium A Pd G3 (240 mg, 0.33 mmol, 0.2 equiv) and K2CO3 (683 mg, 4.94 mmol, 3 equiv) in DME/H2O(6.7 mL, 10: 1) was stirred for 4 h at 85 °C. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%) to afford the title compound (600 mg). Step 6: tert-butyl (tert-butoxycarbonyl)(3-(l-(4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)- ethynyl)naphthalen- 1 -yl)-2-(methylsulfonyl)-8,9-dihydro- 10H-7-oxa- 1,3,6,10- tetraazacyclo-hepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

A solution of tert-butyl (tert-butoxycarbonyl)(3-(l-(4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa- l,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (500 mg, 0.557 mmol, 1 equiv) and m-CPBA (249 mg, 1.225 mmol, 2.2 equiv, 85%) in DCM (5 mL) was stirred for 2 h at RT. The reaction was quenched with sat. Na2S20s aq. solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-70%) to afford the title compound (340 mg).

Step 7: ((3S,7aR)-7a-(((10-(l-(2-(bis(tert-butoxycarbonyl)amino)pyridin-3-yl)ethyl)-4- fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9,10-dihydro-8H-7-oxa- l,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl morpholine-4-carboxylate

To a solution of tert-butyl (tert-butoxycarbonyl)(3-(l-(4-fluoro-5-(7-fluoro-8- ((trii sopropyl silyl)ethynyl)naphthalen- 1 -yl)-2-(m ethyl sulfonyl)-8, 9-dihydro- 10H-7-oxa- 1 ,3 ,6, 10-tetraazacyclohepta[de]naphthalen- 10-yl)ethyl)pyridin-2-yl)carbamate (150 mg, 0.161 mmol, 1.0 equiv) and ((3S,7aR)-7a-(hydroxymethyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl morpholine-4-carboxylate (72 mg, 0.241 mmol, 1.5 equiv) in dioxane (1.5 mL) was added t-BuONa (47 mg, 0.483 mmol, 3.0 equiv) in portions at 0-5 °C and the resulting mixture was stirred for 2 h at RT. The reaction was quenched with sat. NEUCl aq. at 0-5 °C and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-90%) to afford the title compound (115 mg).

Step 8: ((3S,7aR)-7a-(((10-(l-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)ethyl)-5-(8- ethynyl-7-fluoronaphthalen- 1 -yl)-4-fluoro-9, 10-dihydro-8H-7-oxa- 1,3,6,10- tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH-pyrrolizin- 3-yl)methyl morpholine-4-carboxylate

A mixture of ((3S,7aR)-7a-(((10-(l-(2-(bis(tert-butoxycarbonyl)amino)pyridin-3- yl)ethyl)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9,10-dihydro- 8H-7-oxa- 1 ,3,6, 10-tetraazacyclohepta [de]naphthalen-2-yl)oxy)methyl)-6- methylenehexahydro-lH-pyrrolizin-3-yl)methyl morpholine-4-carboxylate (120 mg, 0.105 mmol, 1.0 equiv) and CsF (80 mg, 0.525 mmol, 5 equiv) in DMF (1.2 mL) was stirred for 2 h at RT. The reaction mixture was then diluted with water and extracted with EtOAc.

The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to provide the title compound (80 mg).

Step 9 : ((3 S,7aR)-7a-((( 10-( 1 -(2-aminopyri din-3 -yl)ethyl)-5 -(8 -ethynyl-7- fluoronaphthalen- 1 -yl)-4-fluoro-9, 10-dihydro-8H-7-oxa- 1,3,6,10- tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH-pyrrolizin- 3-yl)methyl morpholine-4-carboxylate

To a solution of ((3S,7aR)-7a-(((10-(l-(2-((tert-butoxycarbonyl)amino)pyridin-3- yl)ethyl)-5-(8-ethynyl-7-fluoronaphthalen-l-yl)-4-fluoro-9,10-dihydro-8H-7-oxa- 1,3, 6,10- tetraazacyclo-hepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl morpholine-4-carboxylate (132 mg, 0.175 mmol, 1.0 equiv) in DCM (1.3 mL) was added HC1 solution (4.0 M in 1,4-dioxane, 1.3 mL) dropwise at 0°C and the resulting mixture was stirred for 1 h at 0°C. The mixture was basified to pH=7 by adding a solution of ammonia in MeOH. The resulting mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC to afford the title compound (16.2 mg). MS (ES, m/z): [M+H]⁺ =789.3.

Example 2

Synthesis of ((3S,7aS)-7a-(((10-((R)-l-(2-aminopyridin-3-yl)ethyl)-5-(8-ethynyl-7- fluoronaphthalen- 1 -yl)-4-fluoro-9, 10-dihydro-8H-7-oxa- 1,3,6,10- tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH-pyrrolizin- 3-yl)methyl morpholine-4-carboxylate (la) and ((3S,7aS)-7a-(((10-((S)-l-(2- aminopyridin-3-yl)ethyl)-5-(8-ethynyl-7-fluoronaphthalen-l-yl)-4-fluoro-9,10-dihydro- 8H-7-oxa- 1 ,3,6, 10-tetraazacyclohepta[de] naphthal en-2-yl)oxy)methyl)-6- methylenehexahydro-lH-pyrrolizin-3-yl)methyl morpholine-4 carboxylate (lb)

A mixture of of ((3S,7aS)-7a-(((10-((R)-l-(2-aminopyridin-3-yl)ethyl)-5-(8- ethynyl-7-fluoronaphthalen- 1 -yl)-4-fluoro-9, 10-dihydro-8H-7-oxa- 1,3,6,10- tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH-pyrrolizin- 3-yl)methyl morpholine-4-carboxylate and ((3S,7aS)-7a-(((10-((S)-l-(2-aminopyridin-3- yl)ethyl)-5-(8-ethynyl-7-fluoronaphthalen-l-yl)-4-fluoro-9,10-dihydro-8H-7-oxa- 1,3, 6,10- tetraazacycloheptafde] naphthalen-2-yl)oxy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl morpholine-4 carboxylate (30 mg) was purified by Supercritical fluid chromatography (SFC) with the following conditions (Column: XA-CHIRAL ART Cellulose-SC, 3*25cm 5um; Mobile Phase A: CO2, Mobile Phase B: MEOH: DCM=2: 1(0.1% 2M NH3-MeOH); Flow rate: 80 mL/min; Gradient: isocratic 50% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm to give compound la and lb. One of la and lb has tR 9.2 min (13 mg) and the other one has tR 11.3 mins (15 mg).

Biological Examples Example 1 p-ERK Cellular 1-plate Assay

The ability of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (test compound) to inhibit K~Ras G 12V activity can be tested using SW620 cell line cell lines which harbor KRAS G12V mutation as described below.

KRAS 3D Spheroid Cell Proliferation Assays. SW620 cells are seeded into 96- well round black/clear bottom, ultra-low attachment surface plate in 100 pl cell culture medium (DMEM with 10% FBS). After 3 days incubation at 37 °C and 5% CO2, compounds solubilized in DMSO are added by Tecan D300e dispenser (0.5% DMSO final). The cells were incubated for 4 days at 37 °C and 5% CO2. Cell proliferation is quantitated by addition of 50 pl/well of CellTiter-Glo® 3D reagent (Promega). The solutions are well mixed by shaking the plate for 10 minutes using an orbital plate shaker and then incubated at room temperature for a total of 30 minutes. After incubation, luminescence is measured on an EnVision multimode plate reader (PerkinElmer). The results are normalized to percentage inhibition with DMSO control as 0% inhibition. The normalized luminescence results are plotted against compound concentration, and the data fit to 4-Parameter Logistic Model to calculate the IC50 by XLfit 5.5.0. The results of the assay are shown in Table 2, below. Table 2. Inhibitory activity in SW620 3D Spheroid Cell Proliferation Assay.

Formulation

Examples

The following are representative pharmaceutical formulations containing a compound of the present disclosure.

Tablet Formulation

The following ingredients are mixed intimately and pressed into single scored tablets.

Ingredient Quantity per tablet (mg) compound Formula (I) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation

The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per capsule (mg) compound Formula (I) 200 lactose spray dried 148 magnesium stearate 2

Injectable Formulation

Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then ncorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. Nasal spray solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims

What is Claimed:

1. A compound of F ormula (I) :

wherein:

X is N or CH;

R⁵ is hydrogen, cycloalkyl, aryl, fused cycloalkyl, heteroaryl, heterocyclyl, or fused heterocyclyl, wherein cycloalkyl, aryl, heteroaryl, fused cycloalkyl, heterocyclyl, and fused heterocyclyl are substituted with R¹⁷, R¹⁸, and R¹⁹ independently selected from hydrogen, alkyl, alkoxylalkyl, halo, haloalkyl, oxo, CN, 0R^ee, -S(O)_nR^ff, -C(0)NR^ssR^bh, - OC(O)NR"R¹¹, and 'NR^kkR^mm where R^ee, R^gg, R^, R", R^jj, R^kk and R^mm are indendently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or alkoxylalkyl; and R^ff is alkyl, haloalkyl, cycloalkyl, heteroalkyl, or alkoxylalkyl; or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. A method of treating cancer in a patient comprising administering to the patient, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of claim 2.

4. The method of claim 3, wherein the cancer is non-small ceil lung cancer, colorectal cancer, or pancreatic cancer.

5. The method of claim 3 or 4, wherein the compound of claim 1, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of claim 2 is administered in combination with at least one additional anticancer agent.