CA3228310A1 - Heterocyclic compounds and methods of use - Google Patents

Heterocyclic compounds and methods of use Download PDF

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Publication number
CA3228310A1
CA3228310A1 CA3228310A CA3228310A CA3228310A1 CA 3228310 A1 CA3228310 A1 CA 3228310A1 CA 3228310 A CA3228310 A CA 3228310A CA 3228310 A CA3228310 A CA 3228310A CA 3228310 A1 CA3228310 A1 CA 3228310A1
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CA
Canada
Prior art keywords
fluoro
methoxy
pyrido
pyrrolizin
fluorotetrahydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CA3228310A
Other languages
French (fr)
Inventor
Michael M. YAMANO
Yunxiao Li
Primali NAVARATNE
Jose Medina
Ning Chen
Liping Pettus
Rene Rahimoff
Xiaofen Li
John Stellwagen
Francesco Manoni
Kexue Li
Brian Alan Lanman
Ryan Paul Wurz
Wei Zhao
Huan RUI
Josephine ESHON
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Amgen Inc
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Amgen Inc
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Publication of CA3228310A1 publication Critical patent/CA3228310A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present disclosure provides compounds useful for the inhibition of KRAS G12D. The compounds have a general Formula (I) : wherein the variables of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.

Description

2 HETEROCYCLIC COMPOUNDS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application No.
63/231,543, filed August 10, 2021 and U.S. Provisional Patent Application No.
63/289,579, filed December 14, 2021, each of which is incorporated by reference in its entirety.
FIELD
The present disclosure provides compounds having activity as inhibitors of mutant KRAS protein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods of treating certain disorders, such as cancer, including but not limited to Non-Small Cell Lung Cancer (NSCLC), colorectal cancer and/or pancreatic cancer.
BACKGROUND
From its identification as one of the first human oncogenes in 1982 (Der et al., 1982), -- KRAS (the Kirsten rat sarcoma viral oncogene homologue) has been the focus of extensive academic and industrial research, as a key node in the MAPK signal transduction pathway, as a transforming factor in a network of parallel effector pathways (e.g., PI3K/AKT) (Vojtek et al., 1998) and as a potential target for anti-cancer agents (Malumbres et al., 2003). Despite progress in the development of inhibitors of upstream and downstream nodes in the MAPK
pathway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014) and MOK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition.
KRAS is a G-protein that couples extracellular mitogenic signaling to intracellular, pro-proliferative responses. KRAS serves as an intracellular "on/off' switch.
Mitogen stimulation induces the binding of GTP to KRAS, bringing about a conformational change which enables the interaction of KRAS with downstream effector proteins, leading to cellular proliferation. Normally, pro-proliferative signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state.
Mutations in KRAS impair the regulated cycling of KRAS between these GDP- and GTP-bound states, leading to the accumulation of the GTP-bound active state and dysregulated cellular proliferation (Simanshu et al., 2017).

Attempts to develop inhibitors of mutated KRAS proteins have historically been thwarted by the absence of druggable pockets on the surface of the protein (Cox et al., 2014).
In 2013, Shokat and colleagues identified covalent inhibitors of a common (O'Bryan, 2019) oncogenic mutant of KRAS, KRAS G12C, which bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented its subsequent activation (Ostream et al., 2013). This discovery brought about significant new efforts in the KRAS
inhibitor research, which have recently culminated in the entry of KRAS inhibitors in human clinical trials.
While some progress has been made on KRAS G12C inhibitors, there is a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A or G12S. Thus, there is a need to develop new inhibitors for KRAS G12D, G12V, G12A, G12S or G12C for the treatment of disorders, such as cancer.
SUMMARY
In one aspect, the present application is directed to compound of formula (I):
X (Rx) ) P
nµ W
N N

Ri I
%L N

(I) or a pharmaceutically acceptable salt of said compound, wherein;
--- is a single bond or a double bond;
W is C, CH or N, wherein when W is CH or N, --- is a single bond;
X is CH2 or CH=CH;
n is 0, 1 or 2;
m is 0,1 or 2;
p is 0, 1, 2, 3 or 4;
each Rx is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C14 alkyl, C1-4 alkoxy, C14 haloalkyl, C14 haloalkoxy, C3-6 cycloalkyl, 5-7 membered heteroaryl, -T-RY or two Rx taken together with adjacent carbon atoms can form C3_7 cycloalkyl, a 5-7 membered
- 3 -heterocycloalkyl, wherein each C3_7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of RY or two W taken together can form a bridged ring where the bridge is selected from one of the following: -C14 alkylene, -C14 alkylene-O-C14 alkylene-, -0-, -S- or -C14 alkylene-S-C14 alkylene- and wherein each C1-4 alkylene is further substituted with 0-2 occurrences of W;
L is C1_6 alkylene, -0-C1_6 alkylene, -S-C1_6 alkylene, NW, 0 or S, wherein each C1_6 alkylene, -0-C1_6 alkylene and -S-C1_6 alkylene chain is substituted with 0-2 occurrences of R2;
W is hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycloalkyl substituted with 0-3 occurrences of R5;
R2 is halogen, hydroxyl, C1-4 alkyl or two R2 on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl;
R3 is aryl or heteroaryl substituted with 0-3 occurrences of R6;
R4 is hydrogen, hydroxyl, halogen, C1-4 alkyl, C14 alkoxy, C1-4 haloalkyl, C24 alkenyl, C24 alkynyl, C3_7 cycloalkyl or cyano;
each R5 is halogen, oxo, hydroxyl, amino or C1_4 alkyl;
each R6 is halogen, hydroxyl, cyano, -N(W)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl;
T is Ci_4 alkylene, -S(0)2-, -C(0)-, -C14 alkylene-C(0)-, -N(H)-C(0)-, -N(H)-S(0)2-, C1-4 alkylene-S(0)2- or -S-;
RY is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, hydroxyl, cyano or -N(W)2; and W is hydrogen or C14 alkyl.
In a second aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient.
In a third aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition as described herein for use in treating cancer (e.g., NSCLC, colorectal cancer or pancreatic cancer).
Reference will now be made in detail to embodiments of the present disclosure.
While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described
- 4 -embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.
DETAILED DESCRIPTION
Provided herein as embodiment 1 is a compound of formula (I):
X
(R') Yrn P t W
N N
Ri I

(I) or a pharmaceutically acceptable salt of said compound, wherein;
--- is a single bond or a double bond;
W is C, CH or N, wherein when W is CH or N, --- is a single bond;
X is CH2 or CH=CH;
n is 0, 1 or 2;
m is 0,1 or 2;
p is 0, 1, 2, 3 or 4;
each Rx is hydroxyl, halogen, oxo, cyano, -N(W)2, C14 alkyl, C14 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 5-7 membered heteroaryl, -T-RY or two W taken together with adjacent carbon atoms can form C3-7 cycloalkyl, a 5-7 membered heterocycloalkyl, wherein each C3-7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of W or two Rx taken together can form a bridged ring where the bridge is selected from one of the following: -C14 alkylene, -C14 alkylene-O-C14 alkylene-, -0-, -S- or -C14 alkylene-S-C14 alkylene- and wherein each C1-4 alkylene is further substituted with 0-2 occurrences of W;
L is Ci_6 alkylene, -0-Ci_6 alkylene, -S-Ci_6 alkylene, NW, 0 or S, wherein each C1_6 alkylene, -0-C1_6 alkylene and -S-C1_6 alkylene chain is substituted with 0-2 occurrences of R2;
- 5 -RI is hydroxyl, aryl, heteroaryl, C3_8 cycloalkyl or heterocycloalkyl substituted with 0-3 occurrences of R5;
R2 is halogen, hydroxyl, C14 alkyl or two R2 on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl;
R3 is aryl or heteroaryl substituted with 0-3 occurrences of R6;
R4 is hydrogen, hydroxyl, halogen, C14 alkyl, C14 alkoxy, C14 haloalkyl, C24 alkenyl, C24 alkynyl, C3_7 cycloalkyl or cyano;
each R5 is halogen, oxo, hydroxyl, amino or C14 alkyl;
each R6 is halogen, hydroxyl, cyano, -N(Rz)2, C14 alkyl, C14 alkoxy, C14 haloalkyl, C14 haloalkoxy, C24 alkynyl or C3_6 cycloalkyl;
T is C14 alkylene, -S(0)2-, -C(0)-, -C14 alkylene-C(0)-, -N(H)-C(0)-, -N(H)-S(0)2-, C14 alkylene-S(0)2- or -S-;
RY is halogen, C14 alkyl, C14 alkoxy, C14 haloalkyl, hydroxyl, cyano or -N(Rz)2; and Rz is hydrogen or C14 alkyl.
Provided herein as embodiment 2 is the compound according to embodiment 1, wherein L is C1_6 alkylene (e.g., methylene or ethylene) substituted with 0-2 occurrences of R2. Provided herein as embodiment 3 is the compound according to embodiment 1, wherein L is -0-Ci_6 alkylene (e.g., -0-methylene-, -0-ethylene- or -0-n-propylene) substituted with 0-2 occurrences of R2. Provided herein as embodiment 4 is the compound according to embodiment 3, wherein L is -0-ethylene or -0-n-propylene substituted with 0-2 occurrences of R2. Provided herein as embodiment 5 is the compound according to embodiment 4, wherein L is -0-ethylene substituted with 0 occurrences of R2.
Provided herein as embodiment 6 is the compound according to any one of embodiments 1-5, wherein RI is heterocycloalkyl substituted with 0-3 occurrences of R5.
Provided herein as embodiment 7 is the compound according to embodiment 6, wherein RI is 7-(hexahydro-1H-pyrrolizine) substituted with 0-3 occurrences of R5. Provided herein as embodiment 8 is the compound according to embodiment 7, wherein RI is 7-(hexahydro-1H-pyrrolizine) substituted with 0 occurrences of R5. Provided herein as embodiment 9 is the compound according to embodiment 7, wherein RI is 7-(hexahydro-1H-pyrrolizine) substituted with 1 occurrence of R5. Provided herein as embodiment 10 is the compound according to embodiment 9, wherein R5 is halogen (e.g., fluorine).
- 6 -Provided herein as embodiment 11 is the compound according to embodiment 6, wherein RI is 2-pyrrolidine or 3-pyrrolidine substituted with 0-3 occurrences of R5. Provided herein as embodiment 12 is the compound according to embodiment 11, wherein RI
is 3-pyrrolidine substituted with 1 occurrence of R5. Provided herein as embodiment 13 is the compound according to embodiment 12, wherein R5 is cyano. Provided herein as embodiment 14 is the compound according to embodiment 11, wherein RI is 3-pyrrolidine substituted with 2 occurrences of R5. Provided herein as embodiment 15 is the compound according to embodiment 14, wherein one R5 is methyl and the other R5 is cyano.
Provided herein as embodiment 16 is the compound according to embodiment 11, wherein RI is 2-pyrrolidine substituted with 2 occurrences of R5. Provided herein as embodiment 17 is the compound according to embodiment 16, wherein R5 is C14 alkyl (e.g., methyl), oxo, cyano or halogen (e.g., fluorine). Provided herein as embodiment 18 is the compound according to embodiment 16, wherein one R5 is methyl and the other R5 is fluorine. Provided herein as embodiment 19 is the compound according to embodiment 16, wherein one R5 is methyl and the other R5 is oxo.
Provided herein as embodiment 20 is the compound according to embodiment 3, wherein L is -0-n-propylene substituted with 2 occurrences of R2. Provided herein as embodiment 21 is the compound according to embodiment 20, wherein the two R2 are taken together with the same carbon atom to form a C3_7 cycloalkyl (e.g., cyclopropyl). Provided herein as embodiment 22 is the compound according to embodiment 21, wherein RI
is heterocycloalkyl (e.g., N-morpholinyl) substituted with 0-3 occurrences of R5.
Provided herein as embodiment 23 is the compound according to embodiment 21, wherein RI
is hydroxyl.
Provided herein as embodiment 24 is the compound according to any one of Ok sovs%
Ok embodiments 1-23, wherein -L-R1 is
- 7 -F

F..-0 k CN H HOok A
AscVitNH o , or Provided herein as embodiment 25 is the compound according to embodiment 24, k F.,..01 0 wherein -L-le is or Provided herein as embodiment 26 is the compound according to embodiment 24, wherein -L-le is . Provided herein as embodiment 27 is the compound N
according to embodiment 24, wherein -L-le is . Provided herein as embodiment 28 is the compound according to embodiment 24, wherein -L-le is Z-1%.6.0k . Provided herein as embodiment 29 is the compound according to N Ok embodiment 24, wherein -L-le is .
Provided herein as embodiment 30 is the
- 8 -.040.
' 0 compound according to embodiment 24, wherein -L-R1 is = .
Provided herein as embodiment 31 is the compound according to embodiment 24, wherein -L-R1 is FiliCr k = . Provided herein as embodiment 32 is the compound according to 0/Th embodiment 24, wherein -L-R1 is .
Provided herein as embodiment 33 is the C N
compound according to embodiment 24, wherein -L-R1 is . Provided herein as embodiment 34 is the compound according to embodiment 24, wherein -L-R1 is C N
= H
. Provided herein as embodiment 35 is the compound according to A N
embodiment 24, wherein -L-R1 is (3t:t o . Provided herein as embodiment 36 is H
AO Cy5 N 0 the compound according to embodiment 24, wherein -L-R1 is .
Provided herein as embodiment 37 is the compound according to embodiment 24, wherein -L-R1 is HOok Provided herein as embodiment 38 is the compound according to any one of embodiments 1-37, wherein R3 is aryl (e.g., phenyl or naphthyl) substituted with 0-3 occurrences of R6.
Provided herein as embodiment 39 is the compound according to any one of embodiments 1-37, wherein R3 is naphthyl substituted with 1 occurrence of R6.
Provided herein as embodiment 40 is the compound according to embodiment 39, wherein R6 is halogen, amino, C14 alkyl (e.g., methyl), C14 haloalkyl (e.g., trifluoromethyl or
- 9 -difluoromethyl), hydroxyl or C2_4 alkynyl (e.g., ethynyl). Provided herein as embodiment 41 is the compound according to embodiment 40, wherein R6 is hydroxyl.
Provided herein as embodiment 42 is the compound according to embodiment 38, wherein R3 is naphthyl substituted with 2 occurrences of R6. Provided herein as embodiment 43 is the compound according to embodiment 42, wherein R6 is C14 alkyl, C24 alkynyl, C3-6 cycloalkyl, halogen, hydroxyl or -N(W)2. Provided herein as embodiment 44 is the compound according to embodiment 43, wherein R6 is ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl or -NH2. Provided herein as embodiment 45 is the compound according to embodiment 43, wherein one R6 is ethynyl and the other R6 is hydroxyl.
Provided herein as embodiment 46 is the compound according to embodiment 43, wherein one R6 is ethyl and the other R6 is hydroxyl. Provided herein as embodiment 47 is the compound according to embodiment 43, wherein one R6 is ethyl and the other R6 is fluorine. Provided herein as embodiment 48 is the compound according to embodiment 43, wherein both R6 are fluorine.
Provided herein as embodiment 49 is the compound according to embodiment 43, wherein one R6 is cyclopropyl and the other R6 is hydroxyl. Provided herein as embodiment 50 is the compound according to embodiment 43, wherein one R6 is fluorine and the other R6 is hydroxyl. Provided herein as embodiment 51 is the compound according to embodiment 43, wherein one R6 is chlorine and the other R6 is -NH2. Provided herein as embodiment 52 is the compound according to embodiment 43, wherein one R6 is ethynyl and the other R6 is fluorine.
Provided herein as embodiment 53 is the compound according to embodiment 38, wherein R3 is naphthyl substituted with 3 occurrences of R6. Provided herein as embodiment 54 is the compound according to embodiment 53, wherein R6 is C14 alkyl, C24 alkynyl, halogen or hydroxyl. Provided herein as embodiment 55 is the compound according to embodiment 54, wherein R6 is ethyl, ethynyl, fluorine or hydroxyl. Provided herein as embodiment 56 is the compound according to embodiment 54, wherein one R6 is hydroxyl, another R6 is ethyl and the final R6 is fluorine. Provided herein as embodiment 57 is the compound according to embodiment 54, wherein one R6 is hydroxyl, another R6 is ethynyl and the final R6 is fluorine. Provided herein as embodiment 58 is the compound according to embodiment 54, wherein two R6 are halogen (e.g., fluorine or chlorine) and the other R6 is hydroxy.
- 10 -Provided herein as embodiment 59 is the compound according to embodiment 38, wherein R3 is phenyl substituted with 3 occurrences of R6. Provided herein as embodiment 60 is the compound according to embodiment 59, wherein one R6 is hydroxyl, another R6 is cyclopropyl and the final R6 is chlorine.
Provided herein as embodiment 61 is the compound according to any one of embodiments 1-37, wherein R3 is heteroaryl (e.g., 4-(1H-indazole) or 4-benzo[d]thiazoly1) substituted with 0-3 occurrences of R6. Provided herein as embodiment 62 is the compound according to embodiment 61, wherein R3 is 4-(1H-indazole) substituted with 2 occurrences of R6. Provided herein as embodiment 63 is the compound according to embodiment 62, wherein one R6 is methyl and the other R6 is chlorine. Provided herein as embodiment 64 is the compound according to embodiment 61, wherein R3 is 4-benzo[d]thiazoly1 substituted with 2 occurrences of R6. Provided herein as embodiment 65 is the compound according to embodiment 64, wherein one R6 is fluorine and the other R6 is -NH2.
Provided herein as embodiment 66 is the compound according to any one of F F F
F
II rel rti &el ISI
l'W l'W l'W l'W i'W
embodiments 1-65, wherein R3 is OH , OH , OH , OH , OH , F
A F CI
F F F
iii 160 lit 140) I. F
* 0 (10 it it 16140 1101 '' OH , OH , OH IW OH , CI
NH2 , V
CI *I
CI
F
LW N
,___S 101 i OH H2N or HN¨N .
- 11 -Provided herein as embodiment 67 is the compound according to embodiment 66, ill &el rail SI Si &el wherein R3 is OH , OH , OH , OH , OH or OH .
Provided herein as embodiment 68 is the compound according to embodiment 66, wherein R3 is OH . Provided herein as embodiment 69 is the compound according to embodiment 66, wherein R3 is OH .
Provided herein as embodiment 70 is the compound according to embodiment 66, wherein R3 is OH .
Provided herein as embodiment 71 is the compound according to embodiment 66, wherein R3 is OH .
Provided herein as ,41) embodiment 72 is the compound according to embodiment 66, wherein R3 is OH
Provided herein as embodiment 73 is the compound according to embodiment 66, wherein R3
12 *
is OH .
Provided herein as embodiment 74 is the compound according to embodiment A
66, wherein R3 is OH .
Provided herein as embodiment 75 is the compound according F
to embodiment 66, wherein R3 is OH .
Provided herein as embodiment 76 is the compound according to embodiment 66, wherein R3 is . Provided herein as embodiment 77 is the compound according to embodiment 66, wherein R3 is 1101 Provided herein as embodiment 78 is the compound according to embodiment 66, wherein R3 .
. Provided herein as embodiment 79 is the compound according to embodiment CI

66, wherein R3 is OH
Provided herein as embodiment 80 is the compound according
- 13 -j0) CI
to embodiment 66, wherein R3 is NH2 .
Provided herein as embodiment 81 is the V
ci compound according to embodiment 66, wherein R3 is OH .
Provided herein as CI

embodiment 82 is the compound according to embodiment 66, wherein R3 is HN¨N
Provided herein as embodiment 83 is the compound according to embodiment 66, wherein R3 1.1 is H2N
Provided herein as embodiment 84 is the compound according to any one of embodiments 1-83, wherein W is N and --- is a single bond.
Provided herein as embodiment 85 is the compound according to any one of embodiments 1-84, wherein X is CH2.
Provided herein as embodiment 86 is the compound according to embodiment 85, wherein n is 0 and m is 0. Provided herein as embodiment 87 is the compound according to embodiment 86, wherein p is 1. Provided herein as embodiment 88 is the compound according to embodiment 87, wherein Rx is 5-7 membered heteroaryl or -T-R.
Provided herein as embodiment 89 is the compound according to embodiment 87, wherein Rx is 5-7 membered heteroaryl substituted with 0-3 occurrences of R. Provided herein as embodiment 90 is the compound according to embodiment 89, wherein Rx is 1-imidazoly1 substituted with 0 occurrences of R. Provided herein as embodiment 91 is the compound according to embodiment 89, wherein -T-RY is -CH2OH, -C(0)NH2, -CH2C(0)NH2, -CH2S(0)2NH2 or -S(0)2NH2.
- 14 -Provided herein as embodiment 92 is the compound according to embodiment 86, wherein p is 2. Provided herein as embodiment 93 is the compound according to embodiment 92, wherein each W is hydroxyl, C14 alkyl, -T-RY or two W taken together with adjacent carbon atoms form 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of W. Provided herein as embodiment 94 is the compound according to embodiment 93, wherein one Rx is methyl and the other Rx is hydroxyl. Provided herein as embodiment 95 is the compound according to embodiment 93, wherein one Rx is -C(0)NH2 and the other Rx is hydroxyl. Provided herein as embodiment 96 is the compound according to embodiment 92, wherein two Rx taken together with adjacent carbon atoms form a 1-tetrahydrofuranyl or 2-tetrahydrofuranyl substituted with 0 occurrences of R.
Provided herein as embodiment 97 is the compound according to embodiment 86, wherein n is 1 and m is 0 or when n is 0 and m is 1. Provided herein as embodiment 98 is the compound according to embodiment 97, wherein p is 0. Provided herein as embodiment 99 is the compound according to embodiment 97, wherein p is 1. Provided herein as embodiment 100 is the compound according to embodiment 99, wherein Rx is hydroxyl or -T-R. Provided herein as embodiment 101 is the compound according to embodiment 100, wherein W -T-RY is -CH2OH, -CH2S(0)2NH2, -C(0)NH2 or -S(0)2NH2.
Provided herein as embodiment 102 is the compound according to embodiment 97, wherein p is 2. Provided herein as embodiment 103 is the compound according to embodiment 102, wherein W is hydroxyl, halogen, -T-RY or two W are taken together with adjacent carbon atoms form a C3_7 cycloalkyl or 5-7 membered heterocycloalkyl wherein each cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R.
Provided herein as embodiment 104 is the compound according to embodiment 103, wherein both Rx are hydroxyl. Provided herein as embodiment 105 is the compound according to embodiment 103, wherein one Rx is fluorine and the other is -CH2OH. Provided herein as embodiment 106 is the compound according to embodiment 102, wherein two Rx taken together with adjacent carbon atoms form a C3-7 cycloalkyl or a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of W. Provided herein as embodiment 107 is the compound according to embodiment 106, wherein two Rx taken together with adjacent carbon atoms form a cyclobutyl substituted with one occurrence of W. Provided herein as embodiment 108 is the compound according to embodiment 107, wherein W is hydroxyl. Provided herein as
- 15 -embodiment 109 is the compound according to embodiment 106, wherein two Rx taken together with adjacent carbon atoms form a 1-tetrahydrofuranyl or 2-tetrahydrofuranyl substituted with 0 occurrences of R.
Provided herein as embodiment 110 is the compound according to any one of (Rx)plt /m OOH ¨1 Oil4 embodiments 1-83, wherein '+' is +
i¨N
H2N(0)C1 H2NO2S
6 C(0)NH
N
HX SO2NH2 2 (0)NH2 <1 6 , HO
N N N N N N N
HO, OH F
asos/S02N H2 h...../OH 0 ,OH
,Iii, N N N N N N
0µt ,OH
Y---NH2 HO OH HO, ,S02NH2 8 , N N N N N
+ + NH2 + ++
, N
+ .
Provided herein as embodiment 111 is the compound according to embodiment 110, OH
(Rx)pl im O...., wherein .^+^. is + .
Provided herein as embodiment 112 is the X i (Rx)P 1 i m O64 nt W N NH2 compound according to embodiment 110, wherein '4' is + .
- 16 -Provided herein as embodiment 113 is the compound according to embodiment 110, wherein H2N(0)C1 (Rx)pA X )rn n W
dvtiA"- is . Provided herein as embodiment 114 is the compound X ) (Rx)p rnA
n W
according to embodiment 110, wherein =^4^^- is .
Provided herein as embodiment 115 is the compound according to embodiment 110, wherein X
l HOvC(0)NH2 (Rx)p im < >
nt W
-4¨ is + . Provided herein as embodiment 116 is the compound X
(Rx)pA im W
according to embodiment 110, wherein is d`t" .
Provided herein as X
(Rx)pl irn W
embodiment 117 is the compound according to embodiment 110, wherein .4¨

c(o)NH2 is 4" . Provided herein as embodiment 118 is the compound according to X
(Rx)pl irn nµ W
embodiment 110, wherein is +
. Provided herein as embodiment 119 X
(Rx)pl im HO
nµ W
is the compound according to embodiment 110, wherein -4¨ is
- 17 -Provided herein as embodiment 120 is the compound according to embodiment 110, wherein (Rx)pl X )m nt W
-4¨ is "4" . Provided herein as embodiment 121 is the compound X
(Rx)pl im rOµ
44'') W
according to embodiment 110, wherein ¨4¨ is . Provided herein as X ) (Rx) mp n W
embodiment 122 is the compound according to embodiment 110, wherein ="+"-H 0, 0 H
is '+' . Provided herein as embodiment 123 is the compound according to X (Rx)pA )m04.4,S02NH2 W
embodiment 110, wherein is d`t" .
Provided herein as X (Rx) )mp n W
embodiment 124 is the compound according to embodiment 110, wherein -4¨

H
is . Provided herein as embodiment 125 is the compound according to X ,L
(Rx)pA im ,OH
W
embodiment 110, wherein .4¨ is + . Provided herein as X
(Rx)pl irn W
embodiment 126 is the compound according to embodiment 110, wherein -^+^.
- 18 -9µ
\1---N H2 is j+ig . Provided herein as embodiment 127 is the compound according to (Rx)p7X )m n W
embodiment 110, wherein is + "2. Provided herein as X
(Rx)pl irn W
embodiment 128 is the compound according to embodiment 110, wherein HO OH

is . Provided herein as embodiment 129 is the compound according to HO, X (Rx) )mp n W
embodiment 110, wherein -^+^. is . Provided herein as embodiment X
(Rx)pl im nµ W
130 is the compound according to embodiment 110, wherein is ,so2NH2 . Provided herein as embodiment 131 is the compound according to OH
(Rx) )rn nµ W
embodiment 110, wherein Juti^". is + .
Provided herein as embodiment
- 19 -X
(Rx)pl im nµ W
132 is the compound according to embodiment 110, wherein JutiA". is +
.
Provided herein as embodiment 133 is the compound according to embodiment 110, wherein (Rx)pl X )rn nµ W
44^^- is 'n'tft .
Provided herein as embodiment 134 is the compound according to embodiment 85, wherein n is 1 and m is 1. Provided herein as embodiment 135 is the compound according to embodiment 134, wherein p is 0. Provided herein as embodiment 136 is the compound according to embodiment 134, wherein p is 1. Provided herein as embodiment 137 is the compound according to embodiment 136, wherein Rx is hydroxyl, cyano, C14 alkoxy, -N(Rz)2, 5-7 membered heteroaryl or -T-RY. Provided herein as embodiment 138 is the compound according to embodiment 136, wherein Rx is hydroxyl, cyano, methoxy, -NH2, 5-oxazolyl, 4-imidazoly1 or 3-pyrazolyl. Provided herein as embodiment 139 is the compound according to embodiment 137, wherein -T-RY
is -NHC(0)0Me, -S(0)2Me, -NHC(0)Me, -NHC(0)-N(H)CH2CH20Me, -CH2OH, -NHS(0)2Me, -CO2H, -C(0)2Me, 1-isopropanol, -S(0)2NH2, -C(0)NH2, -S(0)2N(H)Me or -C(0)N(H)Me.
Provided herein as embodiment 140 is the compound according to embodiment 134, wherein p is 2. Provided herein as embodiment 141 is the compound according to embodiment 140, wherein Rx is halogen, hydroxyl, C14 alkyl, C14 haloalkyl, C14 alkoxy, C3-7 cycloalkyl, -N(Rz)2 or -T-RY or two Rx taken together with the same carbon atom form a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of R. Provided herein as embodiment 142 is the compound according to embodiment 141, wherein one Rx is fluorine and one Rx is hydroxyl. Provided herein as embodiment 143 is the compound according to embodiment 141, wherein one Rx is methyl and one Rx is hydroxyl. Provided herein as embodiment 144 is the compound according to embodiment 141, wherein one Rx is -NHS(0)2Me and one Rx is methyl. Provided herein as embodiment 145 is the compound
- 20 -according to embodiment 141, wherein one W is -C(0)NH2 and one W is hydroxyl.
Provided herein as embodiment 146 is the compound according to embodiment 141, wherein one W is methoxy and one W is methyl. Provided herein as embodiment 147 is the compound according to embodiment 141, wherein one Rx is -NH2 and one Rx is methyl.
Provided herein as embodiment 148 is the compound according to embodiment 141, wherein one Rx is -NHC(0)0Me and one Rx is methyl. Provided herein as embodiment 149 is the compound according to embodiment 141, wherein one Rx is cyclopropyl and one Rx is hydroxyl. Provided herein as embodiment 150 is the compound according to embodiment 141, wherein one Rx is trifluoromethyl and one Rx is hydroxyl. Provided herein as embodiment 151 is the compound according to embodiment 141, wherein one Rx is difluoromethyl and one Rx is hydroxyl. Provided herein as embodiment 152 is the compound according to embodiment 141, wherein one Rx is -C(0)NH2 and one Rx is methyl.
Provided herein as embodiment 153 is the compound according to embodiment 141, wherein one Rx is -CH2OH and one Rx is chloromethyl. Provided herein as embodiment 154 is the compound according to embodiment 141, wherein both Rx are hydroxyl.
Provided herein as embodiment 155 is the compound according to embodiment 140, wherein two W are taken together with adjacent carbon atoms form a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of W. Provided herein as embodiment 156 is the compound according to embodiment 155, wherein two W are taken together with adjacent carbon atoms to form 1-tetrahydrofuranyl substituted with 0 occurrences of W.
Provided herein as embodiment 157 is the compound according to embodiment 155, wherein two Rx are taken together with adjacent carbon atoms to form 1-pyrrolidinyl or 2-pyrrolidinyl substituted with 1 occurrence of W. Provided herein as embodiment 158 is the compound according to embodiment 157, wherein W is oxo.
Provided herein as embodiment 159 is the compound according to embodiment 134, wherein p is 3. Provided herein as embodiment 160 is the compound according to embodiment 159, wherein one Rx is hydroxyl, halogen, oxo, C1-4 alkyl or two Rx taken together with adjacent carbon atoms can form C3-7 cycloalkyl substituted with occurrences of RY or two Rx taken together can form a bridged ring further substituted with 0-2 occurrences of W. Provided herein as embodiment 161 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx are methyl.
Provided
- 21 -herein as embodiment 162 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx are fluorine. Provided herein as embodiment 163 is the compound according to embodiment 160, wherein one Rx is -C(0)NH2 and the other two Rx are methyl. Provided herein as embodiment 164 is the compound according to embodiment 160, wherein one Rx is oxo and the other two Rx are fluorine. Provided herein as embodiment 165 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx taken together with adjacent carbon atoms form cyclopropyl substituted with 0 occurrences of R. Provided herein as embodiment 166 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx taken together form an ethylene or methylene bridge substituted with 0 occurrences of R. Provided herein as embodiment 167 is the compound according to embodiment 160, wherein one Rx is C(0)NH2 and the other two Rx taken together form an ethylene substituted with 0 occurrences of R.
Provided herein as embodiment 168 is the compound according to any one of X )m 0 F4,000H FnoOH
n W N N N
embodiments 1-83, wherein -4- is + , ="+v +
, , = H H 3 H
0,0H 0NTN
OMe : N%S02Me H 14 N N N N

A
OH NH 2 NH2 Me0 NH OH
0,C(0)NH2 - OMe 0--= 01811 OHM Cr<I
N N N N N N
pH pH H H
s.µ 00,NTOMe 00,N y 0-CF3 0=CHF2 OH

N N N N N
-22 -HOkoL 00,NH2 Fn.µOH
H NJI4'd....

N N N NH N
+ ,+ + '+' +1 F
OH 00,S02Me 00NH2 (500H e1c(0)NH2 N N
+ + d`4" + +
, , , , C'OH n.,OH oNHSO2Me F3C coH F
F
N N N N N N
AN + + + + +
, CI
I, 02Me CO2H .o oo, OH H0.4, HO 4' 0 C
% OH
N N N N N N
=+' + + '+' '+' +
, OH -.N 0-ts1H
o .`µµN oCNH
ci), 0.0H 0001 0)(0 N N N N
+ '+' 414N + +
, , , , F C(0)NH2 .,µC(0)NH2 no=OH 0.0CN 0#S0 NH a N N N N N
+ "+' + +1 *"+"
0.0S02NH2 H0,40 H0,0 MeOn 6.,1OH 0.0S02NHMe N N N N N N
+ + + +' '4". d'4"
, , , , , 0.0S02Me a 0.0C(0)NH2 0.0C(0)NHMe HO

() N N N N N
"+' "4"' + + 41' , , , ,
-23-OH OH
*õ.000H 000H 0.00H H0,40.0,0H odo.C(0)NH2 N N N N N
noC(0)NH2 ,0,,,C(0)NH2 0.0S02N H2 HOjo n U
N N N N N
+ + + + +
61(sIll H
n. t Nt 0 + or +
Provided herein as embodiment 169 is the compound according to embodiment 168, (Rx)pl X )m 0 nµ W N
wherein "4" is +' . Provided herein as embodiment 170 is the compound X ) F4,000H
(Rx)p m n W N
according to embodiment 168, wherein j`+^. is 4" .
Provided herein as embodiment 171 is the compound according to embodiment 168, wherein X 1 (Rx)p FnoOH
l it.n =^4^" is 'IN . Provided herein as embodiment 172 is the compound X y dOH
(Rx)p m n W N
according to embodiment 168, wherein '+' is 'iu . Provided herein as (Rx)pl irn embodiment 173 is the compound according to embodiment 168, wherein =i 6
- 24 -H H
(YO
Me is "+" . Provided herein as embodiment 174 is the compound H
X im 00N,s02me (Rx)pl W
according to embodiment 168, wherein =^4^^- is + .
Provided herein as embodiment 175 is the compound according to embodiment 168, wherein X a(Rx)pl ym HO,, nµ W
dvtiA"- is 4+' .
Provided herein as embodiment 176 is the compound (Rx)pX im 0OH/C(0)NH2 l W
according to embodiment 168, wherein ¨4¨ is . Provided herein as embodiment 177 is the compound according to embodiment 168, wherein X
OMe (Rx)pl im ry nµ W
-"+". is + .
Provided herein as embodiment 178 is the compound (Rx)p1XYrn 110::$
nt W
according to embodiment 168, wherein ¨4¨ is . Provided herein as X
(Rx)pl irn W
embodiment 179 is the compound according to embodiment 168, wherein .4¨

Ciiiiss is "4" . Provided herein as embodiment 180 is the compound according to embodiment
- 25 -Me0ANH
X (Rx) ipl /m CHI
nt W N
168, wherein ."+"- is + . Provided herein as embodiment 181 is the OH
(Rx)p iii n W N
compound according to embodiment 168, wherein -4¨ is Provided herein as embodiment 182 is the compound according to embodiment 168, wherein p H
X 0=CF3 (Rx)p )m n W N
44^^- is 4" . Provided herein as embodiment 183 is the compound pH
X ) 0=CHF2 (Rx)p m A õ
n W N
according to embodiment 168, wherein JvtiA". is +1 . Provided herein as embodiment 184 is the compound according to embodiment 168, wherein .%0DH X (Rx) )mpA õ
n W N
44^^- is 44" . Provided herein as embodiment 185 is the compound H
a=NTOMe X i (Rx)plim ri W N
according to embodiment 168, wherein =^4^^- is +1 .
Provided herein as embodiment 186 is the compound according to embodiment 168, wherein H
X N
(Rx)p il ,m 0-y nt W N
dvtiA"- is +1 . Provided herein as embodiment 187 is the compound
-26-X ycf_ (Rx)p m HO,, l õ i ri W N
according to embodiment 168, wherein =^4^^- is + . Provided herein as embodiment 188 is the compound according to embodiment 168, wherein 00, N H2 X )rn (Rx)pA
n W N
dvtiA"- is 4" . Provided herein as embodiment 189 is the compound F
(Rx)p noOH
X y m F
ri W N
according to embodiment 168, wherein ¨4¨ is -4- . Provided herein as embodiment 190 is the compound according to embodiment 168, wherein X X) (Rx)p )m )L N H2 n W
¨4¨ is . Provided herein as embodiment 191 is the X (Rx) ipl irn H2NA=C
ri W N
compound according to embodiment 168, wherein ¨4¨ is -I- .
Provided herein as embodiment 192 is the compound according to embodiment 168, wherein 0.00H X (Rx) )m "4"
= dvtiA"- is '4". . Provided herein as embodiment 193 is the compound X (Rx)p i irn 0,S02Me ri W N
according to embodiment 168, wherein -4¨ is -IN . Provided herein as embodiment 194 is the compound according to embodiment 168, wherein X 1 (R 00 N H2 x)p im n W N
-"+". is + . Provided herein as embodiment 195 is the compound
-27-(500H
(Rx)p X )m n W
according to embodiment 168, wherein =^4^^- is -faw . Provided herein as X (Rx) )mp n W
embodiment 196 is the compound according to embodiment 168, wherein eA(0)NH2 is + . Provided herein as embodiment 197 is the compound according to X )m OH
(Rx)p n W
embodiment 168, wherein Juti^". is 4" . Provided herein as X (Rx) )mp n W
embodiment 198 is the compound according to embodiment 168, wherein n.µOH
is 4" . Provided herein as embodiment 199 is the compound according to X 00N HSO2Me (Rx)p im n W
embodiment 168, wherein is .^fiv . Provided herein as X
(Rx)pl irn W
embodiment 200 is the compound according to embodiment 168, wherein =i 6 is . Provided herein as embodiment 201 is the compound according to
-28-OH
l X ) (Rx)p m a ril W N
embodiment 168, wherein .4¨ is 'Ai" . Provided herein as embodiment 202 F

eLj¨F
(Rx)p irn n W N
is the compound according to embodiment 168, wherein -4¨ is 4" .
Provided herein as embodiment 203 is the compound according to embodiment 168, wherein CI

X ) 1".
(Rx)pl m HO
nt W N
-4¨ is "IN . Provided herein as embodiment 204 is the compound 00.0O2Me X )rn (Rx)p n W N
according to embodiment 168, wherein ju+^. is 4" . Provided herein as embodiment 205 is the compound according to embodiment 168, wherein oo=CO2H X )m (Rx)p ., n W N
-4¨ is + . Provided herein as embodiment 206 is the compound X OH
(Rx)p )m n W N
according to embodiment 168, wherein -4¨ is + . Provided herein as embodiment 207 is the compound according to embodiment 168, wherein ?
X (Rx) 1pl ., irn (.OH
nt W N
.4¨ is + . Provided herein as embodiment 208 is the compound X (Rx)p iA õ irn HO

according to embodiment 168, wherein ¨4¨ is + .
Provided herein as
- 29 -(Rx)pAX)m n W
embodiment 209 is the compound according to embodiment 168, wherein x)OH
is dtia' . Provided herein as embodiment 210 is the compound according to OH
X ) (Rx)pA m n W
embodiment 168, wherein s .
Provided herein as embodiment X
(Rx)pl /m nµ W
211 is the compound according to embodiment 168, wherein .4¨ is Q
00µ 0 +' . Provided herein as embodiment 212 is the compound according to Q
X
(Rx)pl im 00µ N
nµ W
embodiment 168, wherein s . Provided herein as X
(Rx)pl /m W
embodiment 213 is the compound according to embodiment 168, wherein =i 6 H
N
is + . Provided herein as embodiment 214 is the compound according to
- 30 -,-..C(0)N H2 (Rx)pl X )M
n W
embodiment 168, wherein JutiA". is 4' . Provided herein as X
(Rx)pl im nt W
embodiment 215 is the compound according to embodiment 168, wherein -4¨

no,0 H
is . Provided herein as embodiment 216 is the compound according to 0.0C N X )rn (Rx)p n W
embodiment 168, wherein .4- is 4- .
Provided herein as embodiment X (Rx)pl )m n W
217 is the compound according to embodiment 168, wherein Juti^". is CiS02N H2 . Provided herein as embodiment 218 is the compound according to C(0)NH2 l X ) (Rx)p rn W
embodiment 168, wherein is 4v .
Provided herein as embodiment X
(Rx)pl irn nµ W
219 is the compound according to embodiment 168, wherein .4- is 0.0S02N H2 . Provided herein as embodiment 220 is the compound according to
-31-X
(Rx) 1pl õ im HOko nµ W N
embodiment 168, wherein JutiA". is 4' . Provided herein as embodiment (Rx)pl im nµ W
221 is the compound according to embodiment 168, wherein ¨4¨ is HO( N
+' . Provided herein as embodiment 222 is the compound according to embodiment X (Rx) 1pl õ /m MeOn 168, wherein j'+" is '4"' .
Provided herein as embodiment 223 is the R,OH X )rn (Rx)p n W N
compound according to embodiment 168, wherein -4¨ is 4" .
Provided herein as embodiment 224 is the compound according to embodiment 168, wherein X 0.0S02NHMe (Rx)p )rn n W N
-4¨ is ''+' . Provided herein as embodiment 225 is the X (Rx) ipl ., im 0.0S02Me nt W N
compound according to embodiment 168, wherein -^+^. is .4"
.
Provided herein as embodiment 226 is the compound according to embodiment 168, wherein l X ) (Rx)p rn a nµ W N
dvtiA"- is 44" . Provided herein as embodiment 227 is the compound X i (Rx)pA im 0.0C(0)NH2 according to embodiment 168, wherein -4¨ is +' . Provided
- 32 -herein as embodiment 228 is the compound according to embodiment 168, wherein 0.0C(0)NHMe (Rx)pA X )m n W N
dvtiA"- is + . Provided herein as embodiment 229 is the (Rx)pA im compound according to embodiment 168, wherein ¨I¨ is -IN
Provided herein as embodiment 230 is the compound according to embodiment 168, wherein -X
(Rx) 1 OHpl ., im OH
L 5%
nt W N
-4¨ is + . Provided herein as embodiment 231 is the compound OH
X (Rx)pl ii m 0,0H

according to embodiment 168, wherein ¨I¨ is -1"' . Provided herein as X ) (Rx)p m n W
embodiment 232 is the compound according to embodiment 168, wherein ."^i^"-H040,OH
N
is 4" .
Provided herein as embodiment 233 is the compound according to (Rx)pl im 00,C(0)NH2 nµ W N
embodiment 168, wherein -4¨ is + . Provided herein as (Rx)pl im embodiment 234 is the compound according to embodiment 168, wherein =i 6
- 33 -noC(0)NH2 is .
Provided herein as embodiment 235 is the compound according to (Rx)pAX)m C)'C(0)NH2 n W
embodiment 168, wherein s . Provided herein as X
(Rx)pl im nt W
embodiment 236 is the compound according to embodiment 168, wherein es.
is 4v . Provided herein as embodiment 237 is the compound according to (Rx)pl n W
embodiment 168, wherein -^+^. is 4" . Provided herein as embodiment X
(Rx)pl im nµ W
238 is the compound according to embodiment 168, wherein s Of LN) "
41 . Provided herein as embodiment 239 is the compound according to cL
X
(Rx)p 9I
l im 0 nµ W
embodiment 168, wherein -^+^. is +
Provided herein as embodiment 240 is the compound according to embodiment 85, wherein n is 1 and m is 2 or n is 2 and m is 1. Provided herein as embodiment 241 is the compound according to embodiment 240, wherein p is 0. Provided herein as embodiment 242 is the compound according to embodiment 420, wherein p is 1. Provided herein as
- 34 -embodiment 243 is the compound according to embodiment 242, wherein W is C1-4 alkyl, C1_4 alkenyl, cyano, hydroxyl, oxo, -N(W)2 or -T-R. Provided herein as embodiment 244 is the compound according to embodiment 243, wherein W is cyano, methyl, oxo, hydroxyl, -NH2, methenyl, -SO2NH2, -NHC(0)Me or -NHC(0)CF2H.
Provided herein as embodiment 245 is the compound according to embodiment 240, wherein p is 2. Provided herein as embodiment 246 is the compound according to embodiment 245, wherein Rx is hydroxy, C1-4 alkyl, halogen or two W are taken together to form a C1-4 alkylene bridged ring further substituted with 0-2 occurrences of R. Provided herein as embodiment 247 is the compound according to embodiment 246, wherein both W
are fluorine. Provided herein as embodiment 248 is the compound according to embodiment 246, wherein one W is hydroxyl and the other W is methyl. Provided herein as embodiment 249 is the compound according to embodiment 246, wherein two W are taken together to form a bridged ring wherein the bridge is methylene further substituted with 0 occurrences of W. Provided herein as embodiment 250 is the compound according to embodiment 246, wherein two Rx are taken together to form a bridged ring wherein the bridge is methylene further substituted with one occurrence of W. Provided herein as embodiment 251 is the compound according to embodiment 250, wherein RY is hydroxyl. Provided herein as embodiment 252 is the compound according to embodiment 246, wherein two W are taken together to form a bridged ring wherein the bridge is methylene further substituted with 2 occurrences of W. Provided herein as embodiment 253 is the compound according to embodiment 252, wherein each RY is methyl or hydroxyl.
Provided herein as embodiment 254 is the compound according to embodiment 240, wherein p is 3. Provided herein as embodiment 255 is the compound according to embodiment 254, wherein Rx is hydroxy, oxo, halogen or two W are taken together to form a C1-4 alkylene bridged ring further substituted with 0-2 occurrences of W.
Provided herein as embodiment 256 is the compound according to embodiment 255, wherein one W is oxo and the other two Rx are fluorine. Provided herein as embodiment 257 is the compound according to embodiment 255, wherein one Rx is hydroxyl and the other two W
are fluorine.
Provided herein as embodiment 258 is the compound according to embodiment 255, wherein one W is hydroxy and the other two Rx are taken together to form a bridged ring wherein the bridge is methylene further substituted with 0 occurrences of W.
- 35 -Provided herein as embodiment 259 is the compound according to embodiment 85, wherein n is 2 and m is 2. Provided herein as embodiment 260 is the compound according to embodiment 259, wherein p is 0. Provided herein as embodiment 261 is the compound according to embodiment 259, wherein p is 2. Provided herein as embodiment 262 is the compound according to embodiment 261, wherein two Rx are taken together to form a bridged ring wherein the bridge is -0-.
Provided herein as embodiment 263 is the compound according to any one of Ho, HO
(Rx)pAXYm 0 e e e nµ W N N N N
embodiments 1-83, wherein '4"" is "IN
, eN CN Ho, C) 0 0,0S02NH2 @ aNHC(0)Me N N N N N
"IN dVIN 41+1 "IN +

CyNHC(0)CHF2 CyNH2 HO(_) 0010H010 i N N N N N
'"+" "I"' "IN "IN "IN
, , , , 6_2N.0FI OH pH F F 1OH
Cy=OH Or-) e- b N N N N N N
"Im 4+1 dwIN -4- 41", aviN 4+
_153 OH F F OIF F pH
4+1 "IN "IN "IN 4+ "IN 4WIN 4WIN
0 e N N
41N or "IN .
- 36 -Provided herein as embodiment 264 is the compound according to embodiment 263, (Rx)pA X )m n W
wherein dvtiA"- is "I'w . Provided herein as embodiment 265 is the compound HO
x ) (Rx)p rnA
n W
according to embodiment 263, wherein =^4^^- is "I" .
Provided herein as X
(Rx)pl irn W
embodiment 266 is the compound according to embodiment 263, wherein =i 6 HO
is "IN . Provided herein as embodiment 267 is the compound according to embodiment X ) (Rx)pl m e nµ W
263, wherein .1 1- is "IN .
Provided herein as embodiment 268 is the CN
X ) (Rx)pl m nt W
compound according to embodiment 263, wherein =^4^^- is "IN .
Provided herein as embodiment 269 is the compound according to embodiment 263, wherein CN
(Rx) )rn nµ W
44^^- is "IN . Provided herein as embodiment 270 is the compound X
(Rx)pA im 0.11$02NH2 W
according to embodiment 263, wherein ¨4¨ is . Provided
- 37 -herein as embodiment 271 is the compound according to embodiment 263, wherein Ng, (Rx)pAx)m n W
-4¨ is "4" . Provided herein as embodiment 272 is the compound AX (Rx)p )rn CyNHC(0)Me n W
according to embodiment 263, wherein =^4^^- is "IN
Provided herein as embodiment 273 is the compound according to embodiment 263, wherein AX (Rx)p )rn NHC(0)CH F2 n W
dvtiA"- is "I" . Provided herein as embodiment 274 is the X
(Rx)pA ,m a NH2 W
compound according to embodiment 263, wherein s "lat Provided herein as embodiment 275 is the compound according to embodiment 263, wherein x 1 (Rx) Im H50 pl nt W
dvtiA"- is . Provided herein as embodiment 276 is the compound X
(Rx)pl im 00t0H
W
according to embodiment 263, wherein s .
Provided herein as embodiment 277 is the compound according to embodiment 263, wherein X ) (Rx)pl M
W
-4¨ is "IN . Provided herein as embodiment 278 is the compound
- 38 -ApH
(Rx)p X )m n W
according to embodiment 263, wherein ju+^. is "1"' . Provided herein as X (Rx) )mp n W
embodiment 279 is the compound according to embodiment 263, wherein =i 6 0.0H
is "1"' . Provided herein as embodiment 280 is the compound according to X
(Rx)p im n W
embodiment 263, wherein is .
Provided herein as embodiment OH
) (Rx) m W
281 is the compound according to embodiment 263, wherein is .
Provided herein as embodiment 282 is the compound according to embodiment 263, wherein OH
x (Rx)p )l m e nµ W
44^^- is 'IN . Provided herein as embodiment 283 is the compound F F OH
(Rx)pl irn W
according to embodiment 263, wherein JvtiA". is "IN
. Provided herein as X
(Rx)pl im W
embodiment 284 is the compound according to embodiment 263, wherein -^+^.
- 39 _ (-5 is "IN .
Provided herein as embodiment 285 is the compound according to embodiment (Rx)p7X )m n W
263, wherein -4¨ is . Provided herein as embodiment 286 is the X ) (Rx)pA m nt W N
compound according to embodiment 263, wherein =^4^^- is +
. Provided herein as embodiment 287 is the compound according to embodiment 263, wherein l X ) (Rx)p rn (-5 nt W
-4¨ is "I" . Provided herein as embodiment 288 is the compound OH
X ) (Rx)pA m (IL) nt W
according to embodiment 263, wherein -4¨ is 4+1 . Provided herein as X
(Rx)pl im nt W
embodiment 289 is the compound according to embodiment 263, wherein is + .
Provided herein as embodiment 290 is the compound according to embodiment F F
(Rx)pl X )rn nt W
263, wherein ."+"- is "IN . Provided herein as embodiment 291 is the
-40-l X ) (Rx)p rn E\-35 W
compound according to embodiment 263, wherein ¨4¨ is "I"
. Provided herein as embodiment 292 is the compound according to embodiment 263, wherein H
X (Rx)p )l m nµ W
dvtiA"- is ""IN . Provided herein as embodiment 293 is the compound l X
(Rx)p m W
according to embodiment 263, wherein ju+^. is + .
Provided herein as X
(Rx)pl im W
embodiment 294 is the compound according to embodiment 263, wherein =i 6 is + .
Provided herein as embodiment 295 is the compound according to any one of embodiments 1-84, wherein X is CH=CH.
Provided herein as embodiment 296 is the compound according to embodiment 295, wherein n is 0 and m is 1. Provided herein as embodiment 297 is the compound according to embodiment 296, wherein p is 1. Provided herein as embodiment 298 is the compound according to embodiment 297, wherein Rx is hydroxyl.
Provided herein as embodiment 299 is the compound according to embodiment 295, wherein n is 1 and m is 1. Provided herein as embodiment 300 is the compound according to embodiment 299, wherein p is 0. Provided herein as embodiment 301 is the compound according to embodiment 299, wherein p is 1. Provided herein as embodiment 302 is the compound according to embodiment 301, wherein Rx is oxo or hydroxyl.
- 41 -Provided herein as embodiment 303 is the compound according to any one of .%0DH (Th (Th¨

(Rx)pl X )m } } ot0H
n W
embodiments 1-83, wherein Juti^". is '4" or Cy0 Provided herein as embodiment 304 is the compound according to any one of embodiments 1-303, wherein R4 is C14 alkyl, C14 alkoxy, hydroxyl, halogen or haloalkyl. Provided herein as embodiment 305 is the compound according to embodiment 304, wherein R4 is C1_4 alkyl or halogen. Provided herein as embodiment 306 is the compound according to embodiment 305, wherein R4 is fluorine.
Provided herein as embodiment 307 is the compound according to embodiment 1, wherein is the compound is a compound of formula (II):
x (Rx)pl nt N N
RI I

Provided herein as embodiment 308 is the compound according to embodiment 1, wherein is the compound is a compound of formula (III):
X
(Rx)pl im nµ W
N N
I
L N

(III).
Provided herein as embodiment 309 is the compound according to embodiment 1, wherein is the compound is a compound of formula (IV):
- 42 -(Rx)p¨r x )m N N
I

(R5)0-3 (IV).
Provided herein as embodiment 310 is the compound according to embodiment 1, wherein is the compound is a compound of formula (V):
(Rx)p¨X11)m n( N N
rs47 I

(R5)0-3 (R6)0-3 (V).
Provided herein as embodiment 311 is the compound according to embodiment 1, wherein the compound is not:
1 -(7-(8-chloronaphth al en-l-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3- ci]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(S)-1-(7-(8-ethy1-7-flitoro-3-hydroxynaph-thalen-1-y1)-8-flutoro-2-(((2R,7aS)-fluo exahydro- 1H-py rroli zi n-7a-yl)methoxy)pyrido [4,3 -dji pyrim idi -4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-Amethoxy)pyrido[4,3-dipyrimidin-4-y1)-3-methylpiperidin-3-ol;
(3R,5S)-5-(47-(8-ethyl-7-f1uoro-3-hydroxynaphtba1en-1-y-1)-8-fluoro-4-(piperidin-1-y1)pyrido14,3-d-lpyrimidin-2-y1)oxy)methy1)-1-tnethy1pyrrolidin-3-o1;
(2R,7aS)-7a-(47-(8-ethy1-7-fluoro-3-hydroxynaplitha1en-1-y1)-84luoro-4-tpiperidin-l-y1)pyrido[4,3-dlpyrimidin-2-y1)oxy)methyphexahydro- I H-pyrrol
-43 -1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-4-ol;
[(3R,5S)-54[7-(8-ethy1-7-fluoro-3-hydroxy-l-naphthyl )-8-fluoro-4-[(3 S)-3-hydroxy-3-m ethyl-1- pi peri dyl]pyrido [4,3-d]pyrimidin-2-yl]oxymethyl ]-1-methyl-pyrrolidin-3-yl] N-methylcarbamate;
(S)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methy1piperidin- 3-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-ol;
(3R,5S)-5-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-y1)pyrido[4,3-d]pyrimidin-2-ypoxy)methyl)-1-methylpyrrolidin-3-y1 methylcarbamate;
(R)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methy1piperidin-3-ol;
(R)-1-(7-(8-ethyny1-7-fluoronaphthalen-l-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(6-(8-ethy1-7-fluoronaphthalen-1-y1)-5-fluoro-3-((hexahydro-1H-pyrrolizin-7a-ypmethoxy)pyrido[4,3-d]pyrimi din-l-y1)-3-methylpiperidin-3-ol ;
(R)-1-(7-(8-ethy1-7-fluoronaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-34)-2-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-((l.R,5S)-3-azabicyclo[3.2.1]octan-3-y1)-8-fluoro-7-(8-fluoronaphthalen-1.-y1)-2-((hexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(piperidin- 1 -yl)pyrido [4,3 -djpyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1.-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-methylpiperidin-1-yppyrido[4,3-d]pyrimidine;
-44 -1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-ol;
1-(7-(5,6-dimethy1-1H-indazol-4-y1)-8-fluoro-2-((hexahydro-IH-pyrroliziri-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-((hexahydro-1.H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-meth),71piperidin-3-ol;
(3R)-1-[7-(8-ethy1-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxyjpyrido[4,3-cl]pyrimidin-4-y1]-3-methyl-piperidin-3-ol;
4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-y1)-8-fluoro-7-(8-fl uoronaphthalen-l-y1)-2-((hexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidine;
4-(2-azabicyclo[4.1.0]heptan-2-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrido [4,3-d] pyrimidine;
(3R,5S)-1-(8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5-methylpiperidin-3-ol;
1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(azocan-1-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-dlpyrimidine;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methox,õ)pyrido[4,3- d]pyrimidin-4-yl)azepan-3-ol;
(R)-1-(748-ethyny1-7-fluoronaphthalen-1.-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-IH-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(3,3-dimethyIpiperidin-l-y1)-8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine;
1-(7-(8-ethylnaphth al en-1-y1)-8-fluoro-2-((hexahydro-1H-pyrroli zin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yI)-3-methylpiperidin-3-ol;
-45 -1-(7-(8-eth3,7nyinaphthalen-1-371)-8-11uoro-2-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
8-(8-fluoro-2-((hexahydro-1H-pyrroli zin-7a-yOmethoxy)-4-(3-hydroxy-3-methylpiperi din-1-yl)pyrido[4,3-d]pyrimi din-7-y1)-1-n aphthonitri le;
.. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaph thalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
(3R,5R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-I-y1)-8-fluoro-2-(02R,7aS)-fluorohexahydro-1H-pyrrol izin-7a-ypmethoxy)pyrido[4,3-d]pyrimidin-4-yl)piperi dine-3,5-diol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-3-methylazepan-3-ol;
1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yOmethoxy)-7-(quinolin-8-y1)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(2-aminobenzo[d]thiazol-4-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(benzo[d]thiazol-4-y1)-8-fluoro-2-((hexahydro- IH-pyrrolizin-7a-yl)methoxy)pyrido[4,3-di pyrimidin-4-y 1)-3-methy 1piperidin-3-ol;
1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yppyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-((tetrahydro-IH-pyrrolizin-7a(5H)- yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(3-(1H-im idazol-1-yl)azetidin-1-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine;
6-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrroli zin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
3-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
3-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H- pyrrol izin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
-46 -1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamide;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-IH-pyrrolizin-7a-ypmethoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carbonitrile;
(3 S,5R)-1-(8-fluoro-7-(8-fl uoronaphthal en-l-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidine-3,5-diol ;
4-(3-(1H-imidazol-1-yl)azetidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H- pyrrol izin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine;
4-(2-(1H-pyrazol-4-yl)pyrrolidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-õ,l)methoxy)pyrido[4,3-d]pyrimidine;
6-(7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
4-(3-(1H-1,2,3-triazol-4-yppiperidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-djpyrimidine;
.. 4-(3-(1H-pyrazol-1-yl)piperidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine;
(3R,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-I H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5-methylpiperidin-3-ol;
(1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-ypmethoxy)pyrido[4,3-d]pyrimidin-4-yppiperidin-3-y1)methanol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-di pyrimidin-4-y1)-6-methylazepan-4-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-(hydroxymethyl)piperidin-4-ol;
2-(8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((tetrahydro-IH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)isoindolin-4-ol;
4-(3,6-dihydropyridin-1(2H)-y1)-8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine;
1-(8-fluoro-7-(8-fluoronaphthalen- 1 -y1)-2-((tetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-ypazepan-4-ol;
-47 -(1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrim idin-4-yl)azepan-3-yl)methanol;
4-(3-(1H-pyrazol-3-yl)piperidin-1.-y1)-8-fluoro-7-(8-fluoronaph thalen-1-y1)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine;
.. 1-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)pheny1)-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-4)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol, 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-y1)-8-fluoro-2-((llexahydro-1H-pyrrolizin-7a-.õ,1)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrol izin-7a-yl)methoxy)-4-(3-(3-methyl-1H-1,2,4- triazol-5-yl)piperidin-1.-y1)pyrido[4,3-d]pyrimidin-7-y1)naphthalen-2-ol;
3-(7-(8-ethyl-7-fluoro-3-hydroxynaph thalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fl uorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-4)-3-azabicyclo[3.2.1]octan-6-ol, 1-(7-(5-cyclopropy1-6-methyl-1H-indazol-4-y1)-8-fluoro-2-((tetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrim idi n -4-y1)-3-m ethylpi peridin-3-ol;
4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-y1)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyridol:4,341pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-y1)-8-flu oro-2-(((2R,7aS)-2-fluorohexahydro-1H-py zin-7a-yl)methoxy)pyri do[4,3-d]pyrim idi n-4-yppiperidine-3-carboxami de;
1-(8-fluoro-7-(3-hydroxymphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)ppido[4,341pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(3R)-1-(7-(6-chloro-5-(2-methylcyclopropy1)-1H-indazol-4-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahyd ro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrim idin-4-y1)-3-methylpiperidin-3-ol (3R)-1-(7-(1H-benzo indazol-4-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-y1)methoxy)pyridol:4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol, 1-(1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidin-3-yl)methanesulfonamide;
-48 -5-ethy1-6-fluoro-4-(8-fluoro-2-W2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(pyridin-4-y1)azetidin-l-y1)pyrido[4,3-d]pyrimidin-7-y1)naphthalen-2-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-IH-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-ypazepane-4-carbonitrile;
.. (3R,5R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1 H-pyrrolizin-7a-yl)methoxy)pyrido[4.3-d]pyrimidin-4-y1)-5-fluoropiperidin-3-ol (3S,4S)-147-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro- 1 H-pyrrolizin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-y1)-4-fluoropiperidin-3-ol, (3R,5S)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS))-2-fluorohexahydro- 1H-pyrrolizin-7a-ypmethoxy)pyrido[4,3-cipyrimidin-4-y1)-5-methylpiperidin-3-ol;
(2R,3R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-2-methylpiperidin-3-ol;
(3R,6R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-methylpiperidin-3-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-(trifluoromethyl)piperidin-3-ol;
3-(difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-yppiperidin-3-ol;
(2S,3R)-1-(7-(8-ethy1-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluoro .. hexahydro- 1H-pyrroli zin-7a-yl)methoxy)pyri do [1,3-d]pyrim idin-4-y1)-2-methylpiperidin-3-ol;
(3R,6S)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-methylpiperidin-3-ol;
-49 -(3R,5R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-5-methylpiperidin-3-ol;
(3R,4S)- 1 -(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen- 1 -y1)-8-fl uoro-2-(02R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-4-methylpiperidin-3-ol;
(3R,4R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-4-methylpiperidin-3-ol;
- 50 -5-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrol izin-7a-yl )methoxy)pyrido [4,3-d]pyrimi din-4-y1)-N-methylpiperidi ne-3-sulfonami de;
2-(1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)isothiazolidine-1,1-dioxide;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-[3-(sulfamoyl am ino)piperidin- I. -yl ]pyri do [4,3-d]pyrimidine;
1-(1-(8-fl uoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yppiperidin-3-4)urea;
N-(1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yppiperidin-3-yl)formamide;
1-(1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)urea;
N-(1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidin-4-y1)fonuamide;
6-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahyd ro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yppiperidin-3-ylsulfarnate;
8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)-4-(3-(methylsulfonyl)azepan-1-yppyrido[4,3-d]pyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methov)-4-(3-(methyl sulfonyl)azocan-1-yl)pyrido [1,3d]pyrimidine;
4-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidine;
1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoronaphthalen-1-yl)pyrido [4,3-d]pyrim id in-4-y1)-3-methylpiperidin-3-ol;
1-(8-fluoro-7-(8-fl uoronaphthalen-l-y1)-2-((1-(pyrrol idin-1-ylmethypcyclopropyl)methoxy)pyrido[1,3-dlipyrimidin-4-y1)-3-mcthylpiperidin-3-ol;
- 51 -(R)-(1-(8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-lH-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidin-3-y1)methanol;
(S)-1-(8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-1H-pyrrol izin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide;
5-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-N,N-dimethy1-5,6,7,8-tetrahydropyrazo1o14,3-c]azepine-2(4H)-carboxamide;
1-(1-(7-(8-chloronaphthalen-l-y1)-8-fluoro-24(tetrahydro-IH-pyrrolizin-7a(5H)-yl)methov)pyrido[4,3-d]pyrimidin4-yppiperidin-3-y1)methanesulfonamide;
1-(1-(7-(8-ethylnaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yOmethanesulfonamide;
3-(7-(8-ethylnaphth al en-l-y1)-8-fluoro-2-((hexahydro-IH-pyrroli zin-7a-yl)methoxy)pyrido [4,3- d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
5-(7-(8-ethylnaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrim idin-4-yl)tetrahydropyrrolo [3,4-c]pyrrole-1,3(2H,3aH)-d lone;
4-(3-(1H-1,2,4-triazol-3-yppiperidin-1-y1)-7-(8-ethylnaphthalen-1-y1)-8-fluoro-((hexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidine;
(3R,5R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidine-3,5-diol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaph thalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fl uorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-4)-8-fluoro-2-0(3R,7aS)-3-(hydroxy-methyptetrahydro-1H-py-rrol izin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-4-y1)-3- methylpiperidin-3-ol ;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaph thalen-1-y1)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3- methyIpiperidin-3-ol;
(R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth al en-1-y1)-8-fluoro-2-(((3R,7aR)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
-52 -(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyphexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fl uorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
5-ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-y1)methoxy)-4- (3-(methylsulfonyl)azepan-1-yl)pyrido[4,3-d]pyrimidin-7-yOnaphthalen-2-ol;
5-ethy1-6-fluoro-4-(8-fluoro-2-(02R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-ypmethoxy)-4- (3-(methylsulfonyl)azocan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
(2R,7aS)-7a-0(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-44(R)-3-hydroxy-3-methylpipe rid in-1-yppyrido [4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrol izin-2-ol, N-(1-(dimethylamino)propan-2-y1)-7-(8-ethy1-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-14(R)-3-hydroxy-3-methylpiperidin-1-yl)ppido[1,3-d]pyrimidine-2-carboxamide;
((3S,7aR)-7a-(((7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido [4,3-d]pyrimidin-2-yl)oxy)methyl)hexahyd ro-1H-pyrrolizin-3-yl)m ethyl dimethylcarbam ate;
03S,7aS)-7a-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-44(R)-3-hydroxy-3-methylpiperidin-1-yppyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-y1)methyl dimethylcarbamate;
(R)-1-(2-((1-((dimethylamino)methypcyclopropypmethoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoropyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(4-(azepan-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(1R,5R,6R)-3-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-01-(pyrrol idin-1-ylmethyl)cycl opropyl)m ethoxy)pyrido [4,3-d]pyrim idi n-4-y1)-3-azabicyclo [3 .2.1]octan-6-ol ;
4-(4-(azocan-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(3RS,5RS)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrol izin-7a(5H)-ypmethoxy)pyrido[4,3-d]pyrimi din-4-y1)-(hydroxymethyl)-3-methylpiperidin-3-ol;
- 53 -(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-((1-(piperidin-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-((1-(morphol inomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
7-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)hexahydro-2,7-naphthyridine-1,3(2H,4H)-dione;
(R)-1-(748-ethy1-7-fluoro-3-hydroxynaphthalen-1.-y1)-8-fluoro-2-0 1-04-mcthylpiperazin-1-yl)methypcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ypazepan-4-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen- -y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ypazepan-3-ol;
2-(1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidin-3-y1)i soth iazol idine-1,1-dioxi de;
4-(4-(3-azabicyclo[3.2.1]octan-3-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
7-(8-ethy1-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-0(2R,7aS)- 2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)-443-(sulfamoylarnino)-1-piperidyl]pyrido[4,3-d]pyrimidine;
5-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-N,N-dimethy1-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide;
(1R,5R,6R)-3-(2-((1-((dimethylarnino)methyl)cyclopropyl)methoxy)-7-(8-ethy1-7-fluoro-3-h ydroxynaphthal en-l-y1)-8-fluoropyrido [4,3-d]pyrim din-4-y1)-3-azabicyclo [3.2. 1]octari-6-ol;
((3R,7aR)-7a-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-44(R)-3-hydroxy-3-methylpiperidin-1-yppyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-ypmethyl dimethylcarbamate;
-54 -(4aR,7aS)-6-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol izin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)hexahydro-1H- pyrrolo[3,4-d]pyridazine-1,4(4aH)-dione;
(R)-1-(2-(3-(dimethylamino)-2,2-dimethylpropoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- y1)-8-fluoropyrido [4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol ;
1-(2-(2-(dimethylamino)ethoxy)-7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)-fluoropyrido[4,3-d]pyrimidin-4-y1)piperidin-3-ol;
(1R,5R,6R)-3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2402R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-Amethoxy)pyrido [4,3-d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
5-(7-(8-ethyriy1-7-fluoro-3-hydroxynaphthalen- I -y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro- 1H-pyrrol izin-7a-yOmethoxy)pyrido [4,3-d]pyri mi din-4-Atetrahydropyrrolo [3,4-c]pyrrole-1,3(2H,3aH)-dione;
6-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
(R)-1-(7-(8-bromo-741 uoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpipe rid i n-3-ol;
3-(7-(8-bromo-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-dlipyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
6-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
5-(7-(8-bromo-7-fluoro-3-hydroxymphthalen-1-y1)-8-fl uoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)tetrahydropyrrolo [3,4-c]pyrrole-1,3(2H,3aH)-dione;
1-(1-(7-(8-ch loro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fl uoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)pyrido[4,3-dlpyrimidin-4-yppiperidin-3-y1)methanesulfonamide;
- 55 -(R)-1-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin- 3-ol;
3-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrim -4-y1)-3-azabicyclo [3.2.1 joctan -6-ol ;
6-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
5-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-yptetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione;
1-(8-fluoro-7-(2-fluoro-5-hydroxypheny1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(8-fluoro-2-((hexahydro-1H -pyrrolizin-7a-yl)methoxy)-7-(5-methy1-1H -indazol-4-yl)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(8-fluoro-7-(6-methy1-1H-indazol-4-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5-hydroxy-2-methylphenyppyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(6-amino-4-methy1-3-(trifluoromethyppyridin-2-y1)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(1-(8-fluoro-7-(naphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yOmethanesulfonamide;
1-( 1-(7-(8-ethynylnaphthalen-l-y1)-8-fluoro-24(hexahydro-1H-pyrrolizin-7a-yl)methov)pyrido[4,3-d]pyrimidin4-yppiperidin-3-y1)methanesulfonamide;
1-( 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-y1)pyrido[4,3-d]pyrimidin-4-y1)piperidin-3-y1)methanesulfonamide;
1-( 1.-(8-fluoro-2-((hexahydro-IH-pyrrolizin-7a-yOmethoxy)-7-(8-(hydroxymethyl)naphthalen-1- yppyrido[4,3-d]pyrimidin-4-yppiperidin-3-y1)methanesulfonamide;
- 56 -1-(7-(8-cyclopropylnaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyridn[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(3-(1H-1,2,4-triazol-3-yppiperidin-l-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-y1)pyrido[4,3-d]pyrimidine;
8-(4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-1-naphthonitrile;
(3aR,6aS)-5-(7-(8-ethy-nylnaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)tetrahydropyrrolo[3,4-c]pyrrole-1 ,3(2H,3aH)-dione;
1-(7-(6-amino-4-methy1-3-(tri fluorome thyl)pyridin-2-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-( -(8-fluoro-7-(8-(fl uoromethypnaphth al en-l-y1)-24(hexahydro-1H-pyrrol izin-7a-yl)methoxy)pyrido [4,3-dlpyrimidin-4-yppiperidin-3-yOme dianesulfonamide;
1-(1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-methylnaphthalen-1-y1)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)pipe rid in-3-yl)methanesulfonamide ;
1-(1-(7-(8-(difluoromethyl)naphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-i)methoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidin-3-yOmethanesulfonamide;
1-(1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-y1)methanesulfonamide;
1-(7-(5,6-dimethy1-1H-indazol-4-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohe xahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-meth),71piperidin-3-ol;
(3R)-1-(7-(8-ethy1-2-fluoro-3-hydrox,õmaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin- 3-ol;
(3R)-1-(7-(5-ethy1-1H-benzo [I] indazol-4-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroli zin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
5-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen- -y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-N-isopropy1-5, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide;
- 57 -5-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3a-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-clione;
(1R,5R,6S,7R)-3-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-.. fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-7-(hydroxymethyl)- 3-azabicyclo[3.2.1]octan-6-ol;
5-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yphexahydro-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione;
(3R,3aR,6aS)-5-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-4)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-(hydroxymethyphexahydropyrrolo[3,4-c]pyrrol-1.(2H)-one;
(3R,6R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)azepane-3,6-diol;
(3R,6S)-1-(7-(8-ethy1-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-ypmethoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3,6-diol;
03S,7aS)-7a-(07-(8-ethy1-7-fluoro-3-hydroxynaphthelen-1-y1)-8-fluoro-44(R)-3-hydroxy-3-methylpiperidin-1-yppyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-y1)methyl morpholine-4-carboxylate;
((3R,7aS)-7a-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-4-0R)-3-hydroxy-3-methylpiperidin-1-yppyrido[4,3-d]ppimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-y1)methyl dimethylcarbamate;
(R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen- 1 -y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-2-01-((dimethylamino)methypcyclopropyl)methoxy)-8-fluoropyrido[4,3-djpyrimidin-4-34)-3-methylpiperidin-3-ol;
5-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-((tetrahydro-IH-pyrrolizin-7a(5H)- yOmethoxy)pyrido[4,3-d]pyrimidin-4-yptetrahydropyrrolo[3,4-clpyrrole-1,3(2H,3aH)-dione; or
- 58 -(3R)-1-(7-(5,6-dimethy1-1H-indazol-4-y1)-2-01-((dimethylamino)methypcyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol.
Provided herein as embodiment 312 is the compound according to embodiment 1, wherein the compound is not:
1-(7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(S)-1-(7-(8-ethy1-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(3R,5S)-5-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-4-(piperidin-1-.. yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ol;
(2R,7aS)-7a-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-4-(piperidin-l-y1)pyrido[4,3-d]pyrimidin-2-ypoxy)methyl)hexahydro-1H-pyrrolizin-2-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-4-ol;
[(3R,5S)-54[7-(8-ethy1-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3S)-3-hydroxy-3-methyl-1- piperidyl]pyrido[4,3-dlipyrimidin-2-ylloxymethy1]-1-methyl-pyrrolidin-3-yl] N-methylcarbamate;
(S)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-.. methylpiperidin- 3-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-ol;
(3R,5S)-5-(07-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-y1)pyrido[4,3-d]pyrimidin-2-ypoxy)methyl)-1-methylpyrrolidin-3-y1 methylcarbamate;
- 59 -(R)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-ethyny1-7-fluoronaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(6-(8-ethy1-7-fluoronaphthalen-1-y1)-5-fluoro-3-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-1-y1)-3-methylpiperidin-3-ol;
(R)-1-(748-ethy1-7-fluoronaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro-IH-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-((1R,5S)-3-azabicyclo[3.2.1]octan-3-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-((hexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-dlpyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(piperidin- 1 -yl)pyrido [4,3 -d]pyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-24(hexahydro-1H-pyrrolizin-7a-yl)methoxy-)-4-(3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidine;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-ol;
1-(7-(5,6-dimethy1-1H-indazol-4-y1)-8-fluoro-2-((hexahydro-IH-pyrroliziri-7a-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-((hexahydro-1.H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-meth),71piperidin-3-ol;
(3R)-1-[7-(8-ethy1-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxyjpyrido[4,3-cl]pyrimidin-4-y1]-3-methyl-piperidin-3-ol;
4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-y1)-8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidine, 4-(2-azabicyclo[4.1.0]heptan-2-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidine;
8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrido [4,3-d] pyrimidine;
-60 -(3R,5 S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((he xahydro-1H-pyrrolizin-7a-yl)methoxy)pyri do [4,3-d]pyrim idin-4-y1)-5-methylpiperidin-3-ol;
1-(7-(2-am ino-5,6-dim ethylbenzo [Obi azol-4-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-py rroli zin-7a(5H)-yl)m ethoxy)pyrido [4,3-d]pyrim idin-4-y1)-3-m ethylpiperidin-3-ol;
1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(azocan-1-y1)-8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahyd ro-1H-py rrolizin-7a-yl)m ethoxy)pyrido[4,3-d]pyrim idine ;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-.õ'1)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-3-ol, (R)-1-(7-(8-ethyny1-7-fluoronaphthale n-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-yl)methoxy)pyri do [4,3-d]pyrimidin-4-y1)-3-methylpiperi 4-(3,3-dimethyIpiperidin-l-y1)-8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine;
1-(7-(8-ethylnaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)m ethoxy)pyrido [4,3- d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(8-ethynylnaphthalen-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
8-(8-fluoro-2-((hexahydro-1H-py rrolizin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-y1)-1-naphthonitri le;
6-(7-(8-ethyl-7-fluoro-3-hydroxynaph thalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fl uorohexahydro-1H- pynol izin-7a-yl)methoxy)pyrido [4,3-d]pyrim idin-4-y1)-6-azabicyclo [3.2.11loctan-3-ol;
(3R,5R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)pipe rid ine-3,5-diol ;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3- d]pyrimidin-4-y1)-3-methylazepan-3-ol;
1-(8-fluoro-2-((hexahydro-1H-py rrolizin-7a-yl)methoxy)-7-(quinolin-8-yl)pyrido d]pyrim idin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(2-aminobenzo [d]thiazol-4-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
- 61 -1-(7-(benzo[d]thiazol-4-4)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d] pyrimidin-4-y 1)-3-methy 1piperidin-3-ol;
1-(8-fluoro-2-((hexahydro-1H-pyrroli zin-7a-yl)methoxy)-7-(naphth alen-l-yl)pyrido [4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(3-(1H-imidazol-1-yl)azetidin-1-y1)-8-fluoro-7-(8-fluoronaph thalen-1-y1)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine;
6-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-.õ,l)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
3-(8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
3-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- dlpyrimidin-4-yppiperidine-3-carboxamide;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carbonitrile;
(3 S,5R)-1-(8-fluoro-7-(8-fluoronaphth al en-l-y1)-2-((hexahydro-1H-pyrrol izin-7a-yl)methoxy)pyrido[4,3-dlpyrimidin-4-yppiperidine-3,5-diol;
4-(3-(1H-imidazol-1-yl)azetidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H- pyrrol izin-7a(5H)-õ,l)methoxy)pyrido[4,3-d]pyrimidine;
4-(2-(1H-pyrazol-4-yl)pyrrolidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine;
6-(7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-azabicyclo[3.2.1]octan-3-ol;
4-(3-(1H-1,2,3-triazol-4-yppiperidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yi)methoxy)pyrido[4,3-d]pyrimidine;
4-(3-(1H-pyrazol-1-yppiperidin-1-y1)-7-(8-chloronaphthalen-1-y1)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine;
-62 -(3R,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-34)-2-((tetrahydro-I H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5-methylpiperidin-3-ol;
(1-(8-fluoro-7-(8-fluoronaphthalen-l-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-ypmethoxy)pyrido[4,3-d]pyrimidin-4-yppiperidin-3-ypmethanol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrroiizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-4-y1)-6-methylazepan-4-ol;
1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cl]pyrimidin-4-y1)-3-(hydroxymethyppiperidin-4-ol;
2-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-.. yl)methoxy)pyrido[4,3-d]pyrimidin-4-ypisoindolin-4-ol;
4-(3,6-dihydropyridin-1(2H)-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidine;
1-(8-fluoro-7-(8-fluoronaphthalen- 1 -y1)-2-((tetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol, (1-(8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-clipyrimidin-4-ypazepan-3-yOmethanol;
4-(3-(1H-pyrazol-3-yl)piperidin-1-y1)-8-fluoro-7-(8-fluoronaphthalen-1-y1)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-õ,l)methoxy)pyrido[4,3-d]pyrimidine, 1-(7-(3-chloro-5-hydroxy-2-((1S,2R)-2-methylcyclopropyl)pheny1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
4-(4-(3-(1H-imidazol-1-yl)azetidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3-(1H-1,2,4-triazol-5-34)piperidin-1-y1)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrroli zin-7a-yl)methoxy)-4-(3-(3-m ethyl-1H-1,2,4- triazol-5-yl)piperidin-1-yppyrido[4,3-d]pyrimidin-7-y1)naphthalen-2-ol;

3-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-6-ol;
1-(7-(5-cyclopropy1-6-methy1-1H-i ndazol-4-y1)-8-fluoro-2-((tetrahydro-1H-pyrrol izin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
-63 -4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-y1)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-IH-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrim idi n-4-yppiperidine-3-carboxami de;
1-(8-fluoro-7-(3-hydroxpiaphthalen-1-y1)-2-((tetrahydro-1H-py rrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(3R)-1-(7-(6-chloro-5-(2-methylcyclopropy1)-1H-indazol-4-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-IH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol;
(3R)-1-(7-(1H-benzo[flindazol-4-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-dlipyrimidin-4-yl)piperidin-3-y1)methanesulfonamide;
5-ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methox-y)-4-(3-(pyri din -4-yl)azeti d in-l-yppyrido [4,3-d]pyrim idin-7-yl)naphthalen-2-ol 1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)azepane-4-carbonitrile;
(3R,5R)-1-(7-(8-ethy1-7-fluo ro-3-h ydroxynaphthal en-1-y1)-8-fluo ro-2-(((2R,7aS)-2-fluorohexahydro-1 H-pyrrolizin-7a-yl)methoxy)pyrido[4.3-d]pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
(3 S,4S)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1 H-pyrrolizin-7a-yl)methoxy)pyrido[4, 3-dipy rim idin-4-y1)-fluoropiperidin-3-ol (3R,5S)-1-(7-(8-ethy1-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-2-(((2R,7aS))-2-fluorohexahydro- 1H-pyrrolizin-7a-y ethoxy)pyrido [4,3-d]pyrim idin-4-y1)-5-methylpiperidin-3-ol;
(2R,3R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro- 1H-pyrrol izin-7a-yl)methoxy)pyrido [4,3-d]pyri mi din-4-y1)-methylpiperidin-3-ol;
-64 -(3R,6R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-6-methylpiperidin-3-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-(trifluoromethyl)piperidin-3-ol;
3-(difluoromethy1)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol;
(2S,3R)-1-(7-(8-ethy1-7-fluoro-3-hydroxy-naphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluoro hexahydro- 1H-pyrrolizin-7a-Amethoxy)pyrido 1,3-d]pyrimidin-4-yl)-2-methylpiperidin-3-(3R,6S)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fl uorohexahydro-1. H-pyrrolizin-7a-yl)methoxy)pyri do [4,3-d]pyrim idin-4-y1)-methylpiperidin-3-ol;
(3R,5R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5-methylpiperidin-3-ol;
(3R,4S)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-y1)-4-methylpipe rid i .. (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-ypmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-4-methylpiperidin-3-ol;
1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5,5-difluoropiperidin-3-ol;
1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-dlipyrimidin-4-y1)-4,4-difluoropiperidin-3-ol;
(3R,5S)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorohexahydro-1H-pyrrolizin-7a-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
- 65 -(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphtbalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-IH-pyrrolizin-7a(5H)-yOmethoxy)pyrido [4,3 -d]pyrimidin-4-yl)piperidi 11 -3 -ol;
5-(7-(8-ethy1-7-fluoro-3-hydroxyTtaph thalen-i-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahy-dro-1H-pyrrolizin-7a(5H)-yOrnethoxy)pyrido [4,3-d]pyrimidin-4-yptetrahydropyrrolo [3,4-c]pyrrole-1,3(2f1,3aH)-dione;
(3R)- I -[7-(8-ethyl -7-fluoro-3-1137droxy-1-naphthyl)-8-fluoro-2-[[ I -(pyrrolidi 11 - -ylmethypcyclopropyllmethoxy]pyrido[4,3-dlpyrirnidin-4-y1]-3-ni ethyl-piperidin-3-ol;
1-(1-(7-(7,8-difluoro-3-hydroxymaplithalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOnnethoxy)pyrido[4,3-dipyrinaidin-4-y1)piperidin-3-yDrnethanesulfonamide; or 841 uoro-7-(8-fluoronaphthalen -1-y1)-4-(3-(pyridin-4-ypazetidi n -1-y1)-2-((tetrahydro-III-pyrrolizin-7a(511)-yOmethoxy)pyrido[4,3-dipyrirnidine.
Provided herein as embodiment 313 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-y0azepan-3-one;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-yOpiperidin-3-ol (Isomer 1);
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
- 66 -(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-azabicyc1o[3.2.11octan-6-o1 (Isomer 2);
.. 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-ol (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-ol;
.. 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-4-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-2,3,6,7-tetrahydro-1H-azepin-3-ol;
4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-fluoropiperidin-3-ol;
.. 4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
- 67 -4-(4-(Azocan-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-5,5 -difluoropiperidin-3 -ol ;
.. (R)-1-(7-(8-Ethy1-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -alpyrimidin-4-yl)pipe ridin-3 -ol ;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol ;
(R)-1-(8-Fluoro-7-(8-fluoro-3 -hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -methylpiperidin-3 -ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-yl)azepane-4-carbonitrile (Isomer 1);
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-01;
rac-(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5 -methylpiperidin-3 -ol ;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yl)azepan-3 -y1)-2,2-difluoroacetamide ;
3 -Ethy1-1-(7-(8-ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpipe ridin-3-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine -3 -sulfonamide; or 1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -(trifluoromethyl)pipe ridin-3 -ol
- 68 -Provided herein as embodiment 314 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-one;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-ol (Isomer 1);
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aR)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 2);
- 69 -1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-ol (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-4-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-2,3,6,7-tetrahydro-1H-azepin-3-ol;
4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
4-(4-(Azocan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-5,5-difluoropiperidin-3-ol;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-01;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-ypazepane-4-carbonitrile (Isomer 1);
- 70 --Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-01 ;
rac-(3R,5 S)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-5 fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]
pyrimidin-4-y1)-5 -methylpiperidin-3 -ol ;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-yl)azepan-3 -y1)-2,2-difluoroacetamide ;
3 -Ethy1-1-(7-(8-ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpipe ridin-3-ol ;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine -3 -sulfonamide; or 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -(trifluoromethyl)pipe ridin-3 -ol Provided herein as embodiment 315 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine -3 -sulfonamide;
4-(4-(Azepan-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-yOpyrrolidine -3 -carboxamide ;
(5)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-yOpyrrolidine-2-carboxamide;
-71 -1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y0azetidine-2-carboxamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-4-carboxamide ;
(5)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-yl)piperidine -3 -sulfonamide;
2-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-y0azetidin-3 -.. yl)acetamide;
3 -(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -azabicyclo [3 .2. 0lheptan-6-01;
(R)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpipe ridin-3 -ol ;
(3S ,4R)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpyrrolidine-3,4-diol ;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-yl)pipe ridin-3 -ol ;
(R)-1-(7-(8-Ethy1-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yl)pipe ridin-3 -ol ;

(5)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpipe ridin-3-ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -methoxypiperidin-l-yl)pyrido [4,3 -al pyrimidin-7-yl)naph thalen-2-ol ;
1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yl)pyrrolidin-3 -ol;
- 72 -(1R,45)-2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-2-azabicyclo [2.2.2loctan-6-ol;
3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-((S)-2-(hydroxymethypazetidin-1-y1)pyrido[4,3-alpyrimidin-7-y1)naphtha1en-2-ol;
4-(4-((1S,5R)-3-Oxa-6-azabicyclo [3.2.01heptan-6-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
re1-4-(4-((1R,5R)-2-Oxa-6-azabicyclo [3.2.01heptan-6-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3-azabicyc1o[3.2.11octan-6-o1 (Isomer 1);
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3-azabicyclo [3.2.11octan-6-o1 (Isomer 2);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
- 73 -(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidin-3-ol;
(3R,65)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-ol;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-8-azabicyclo[3.2.11octan-2-ol 2,2,2-trifluoroacetate;
(3R,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-6-methylpiperidin-3-01;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(hexahydro-5H-furo[2,3-clpyrrol-5-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 2);
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
re1-5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7 aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-blpyridin-4(2H)-yOpyrido[4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
- 74 -(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-(fluoromethyl)piperidin-3-ol (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-(fluoromethyl)piperidin-3-ol (Isomer 2);
(3R)-1-(7-(8-ethy1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol (Isomer 2);
(3R)-1-(7-(8-ethy1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol (Isomer 1);
(3R)-1-(7-(8-A11y1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide;
4-(4-((R)-3-Aminopiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-((S)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-((R)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(3R,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-fluoropiperidin-3-ol;
(R)-1-(7-(7,8-Difluoronaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol;
- 75 -(R)-1-(7-(8-E thyny1-7-fluoronaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol ;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-2-azabicyclo [2 .2. 11heptan-6-ol;
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol ;
(R)-1-(7-(8-Chloro-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol ;
(R)-1-(8-Fluoro-7-(8-fluoro-3 -hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol ;
(R)-1-(7-(8-Ethy1-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol ;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol;
(R)-1-(8-Fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-y1)pyrido [4,3 -d] pyrimidin-4-y1)-3 -me thylpiperidin-3 -ol ;
rel-(3aR,6aS)-5-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yl)hexahydropyrrolo [3 ,4-cl pyrrol-1(2H)-one ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-re/-43aR,7aS)-hexahydrofuro [3 ,2-clpyridin-5 (4H)-yl)pyrido [4,3-cilpyrimidin-7-yl)naphthalen-2-ol;
rel-(3aR,7aR)-4-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-y0octahydro-2H-pyrrolo [3 ,2-b1 pyridin-2-one ;
rel-(3 S,6R)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-6-methylpiperidine-3 -carboxamide ;
- 76 -3 -Ethy1-1-(7-(8-ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpipe ridin-3-ol ;
-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-5 yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-l-y1)pyrido [4,3 -cilpyrimidin-7-yl)naphthalen-2-ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3 -(hydroxymethyl)-3 -methylpipe ridin-l-yl)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3 -methylpiperidine -3 -carboxamide ;
8-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-2-methyl-8-azabicyclo [3 .2.11octan-2-ol;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-2-methyl-8-azabicyclo [3 .2.11octan-2-ol;
2-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-6-methyl-2-azabicyclo [2.2.11heptan-6-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-2-azabicyclo 112.2.11heptan-6-one ;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -d] pyrimidin-4-yOpipe ridin-3-ypacetamide ;
1 - ((R) -1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -d] pyrimidin-4-yOpipe ridin-3-y1)-3 -(2-methoxyethyl)thioure a;
- 77 -N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-yl)methanesulfonamide;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-yl)acetamide;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-yOcarbamate;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-yl)carbamate;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-2-methylazepan-1-y1)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylazepan-1-y1)pyrido[4,3-4 pyrimidin-7-yl)naphthalen-2-ol;
(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azetidin-3-yl)methanesulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-hydroxyazetidine-3-carboxamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-y1)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidine-4-sulfonamide;
- 78 -1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-yOpyrrolidine-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y0azetidine-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y0azetidine-3-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-N-methylpiperidine-3-carboxamide;
-- (5)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-yOpiperidine-3-carboxamide;
4-(4-(3-(1H-Imidazol-1-yl)azetidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylazetidin-3-ol;
4-(4-(Azocan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro--- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-4-one;
rac-(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-azabicyclo[3.2.11octan-8-ol;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-8-methy1-3-azabicyclo[3.2.11octan-8-ol;
- 79 -3 -(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -azabicyclo [4.1. 0] heptan-1-ol ;
rel-(3R,45)-1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpiperidine-3,4-diol ;
rel-(3S,45)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-yOpiperidine-3,4-diol ;
rel-(3aR,7aR)-5-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-y0octahydro-3H-pyrrolo [3 ,4-cl pyridin-3 -one;
4-(4-((S)-3-Aminopiperidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3 -Azabicyclo [3 .2. lloctan-3 -y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3 -(1H-Imidazol-4-yl)pipe ridin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol ;
4-(4-(3 -(1H-Pyrazol-5 -yl)pipe ridin-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -(oxazol-5 -yl)pipe ridin-l-yl)pyrido [4,3 -al pyrimidin-7-yOnaph thalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-1,2,3 ,6-tetrahydropyridin-3 -ol;
N-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpipe ridin-3-yl)methane sulfonamide;
5 -Ethy1-6-fluoro-4-(8-fluoro-4-42S,45)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114,3 -al pyrimidin-7-yl)naphthalen-2-ol ;
- 80 -(3R,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-4-fluoropiperidin-3 -ol ;
-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-5 yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-ol ;
rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5 -fluoropiperidin-3 -ol ;
(3S,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -alpyrimidin-4-yOpyrrolidine-3,4-diol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-5,5 -difluoropiperidin-3 -ol ;
((5)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-yOpyrrolidin-2-yl)methane sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-5,5-difluoroazepan-4-ol;
3 -(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -azabicyclo [3 .2. lloctane -1-carboxamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo [3,4-c] pyrrol-5 (3H)-yl)pyrido [4,3-cilpyrimidin-7-yl)naphthalen-2-ol;
rac-(1S,55)-8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-8-azabicyclo [3 .2. lloctane -2-carboxamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido [4,3 -al pyrimidin-7-yl)naphthalen-2-ol ;
-81 -5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-45)-3-(hydroxymethyl)piperidin-1-y1)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
Methyl (R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-yOpiperidine-3-carboxylate;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-one;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-ol;
(5)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-ol;
4-(4-((R)-3-Aminoazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-3-y1)-2,2-difluoroacetamide;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-3-yl)acetamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-1,2,6,7-tetrahydro-3H-azepin-3-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-2,3,6,7-tetrahydro-1H-azepin-3-ol;
- 82 -1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-ol (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-o1 (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3-dlpyrimidin-4-y1)piperidine-3-carboxylic acid;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-y1)pyrido [4,3 -al pyrimidin-7-yl)naphthalen-2-01;
4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-yl)azepan-4-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-4-methylazepan-4-ol;
4-(4-(4-Aminoazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(4-methyleneazepan-1-y1)pyrido [4,3 -al pyrimidin-7-yOnaphthalen-2-ol;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3-azabicyclo [3 .2.11octane-6-.. carbonitrile (Isomer Mix 1);
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3-azabicyclo [3 .2.11octane-6-carbonitrile (Isomer Mix 2);
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3-azabicyclo [3 .2.21nonane-6-carbonitrile;
- 83 -(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-3 -(methyl-d3)piperidin-3 -ol ;
(S)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-3 -(methyl-d3)piperidin-3 -ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -methoxy-3 -methylpipe ridin-l-yl)pyrido [4,3 -al pyrimidin-7-yl)naphthalen-2-ol ;
4-(4-(4,4-Difluoroazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-5,5 -difluoroazepan-4-one ;
1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cUpyrimidin-4-yl)piperidine-3 -carbonitrile ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3,3 -difluoropiperidin-4-one ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-yl)pipe ridin-4-ol ;
(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5 -(trifluoromethyppipe ridin-3 -ol ;
6-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-6-azabicyclo [3 .2 .11octan-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -(trifluoromethyl)pipe ridin-3 -ol ;
3 -Cyclopropy1-1-(7-(8-ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpipe ridin-3-ol ;
- 84 -1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 - cil pyrimidin-4-yl)azepane-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 - cil pyrimidin-4-y1)-3 -hydroxypipe ridine -3 -carboxamide;
4-(4-(3-((Difluorome thyl)sulfonyl)piperidin-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 - cil pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 - cil pyrimidin-4-y1)-5 -methylpiperidine -3 -carboxamide ;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 - cil pyrimidin-4-yOpiperidine-3 -sulfonamide;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)- 1-(8-Chloro-7-(8-ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(514)-yl)methoxy)pyrido [4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)- 1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido [4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42S, 7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol bis(2,2,2-trifluoroacetate);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol; or (R)- 1-(2-((1-((D imethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-hydroxynaphthalen-l-y1)-8-fluoropyrido [4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol.
- 85 -Provided herein as embodiment 316 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y0azepan-3-one;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yOpiperidin-.. 3-ol (Isomer 1);
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aR)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)piperidin-3-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 2);
- 86 -1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-ol (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-4-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-2,3,6,7-tetrahydro-1H-azepin-3-ol;
4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
4-(4-(Azocan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-5,5-difluoropiperidin-3-ol; or (R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol.
Provided herein as embodiment 317 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-one;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-ol;
- 87 -3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)piperidin-3-ol (Isomer 1);
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)piperidin-3-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol; or 3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-azabicyc1o[3.2.11octan-6-ol (Isomer 2).
Provided herein as embodiment 318 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y0azepan-3-one;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-ol;
- 88 -3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)piperidin-3-ol (Isomer 1);
(R)- 1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol; or 3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)piperidin-3-ol (Isomer 1).
Provided herein as embodiment 319 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-(fluoromethyl)piperidin-3-ol (Isomer 1);
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-ol;
(3R)-1-(7-(8-Ally1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol;
(R)-1-(2-((14(Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoropyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)piperidin-3-ol (Isomer 1);
(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aR)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
- 89 -(3R)-1-(7-(8-ethy1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol (Isomer 2);
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(8-Chloro-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-o1 (Isomer 2);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylazepan-3-ol (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-ol;
- 90 -4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3 S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-5,5-difluoropiperidin-3-ol;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-ol; or N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-3-y1)-2,2-difluoroacetamide.
Provided herein as embodiment 320 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds:
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-ol (Isomer 1);
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (Isomer 1);
-91 -(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(8-Chloro-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-azabicyclo[3.2.11octan-6-o1 (Isomer 2);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylazepan-3-ol (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)-8-methylpyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-01;
4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-fluoropiperidin-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-5,5-difluoropiperidin-3-o1;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rac-(3R,5 S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-methylpiperidin-3-ol; or
- 92 -N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-3-y1)-2,2-difluoroacetamide.
Provided herein as embodiment 321 is the compound according to embodiment 1, wherein the compound is not example 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202, 203, 213, 221, 228, 237, 239, 240, 241, 242, 243, 244, 246, 248, 250, 251, 253, 256, 257, 268, 273, 274, 281, 285, 290, 292, 295, 296, 299, 301, 302, 303, 304, 306, 308, 309, 311, 312, 313, 314, 316, 317, 320, 325, 327, 331, 332, 335, 336, 346, 347, 348, 350, 352, 353, 360, 362, 363, 366, 387, 388, 389, 390, 399, 402, 403, 404, 414, 418, 421, 422, 423, 429, 430, 431, 432, 435, 436, 437, 438, 439, 440, 455, 456, 458, 459, 460, 461, 463, 465, 471, 472, 473, 479, 482, 486, 487, 488, 490, 491, 511, 512, 514, 517, 519 or 520 from international publication No. WO 2022/132200 (International Application No.
PCT/US2021/010065).
Provided herein as embodiment 322 is the compound according to embodiment 1, wherein the compound is not example 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202 or 203 from international publication No. WO 2022/132200 (International Application No.
PCT/US2021/010065).
The foregoing merely summarizes certain aspects of this disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.
Formulation, and Route of Administration While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition. Thus, in one embodiment, provided herein is a pharmaceutical
- 93 -composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V.
Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.
The compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended. The compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. The pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
Provided herein as embodiment 323 is a pharmaceutical composition comprising the compound according to any one of embodiments 1-322, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
Provided herein as embodiment 324 is a compound according to any one of Embodiments 1-322, or a tautomer thereof, or a pharmaceutically acceptable salt of said
- 94 -compound or said tautomer, or the pharmaceutical composition according to embodiment 323 for use as a medicament.
Methods of Use As discussed herein (see, section entitled "Definitions"), the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing.
Accordingly, the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms.
Besides being useful for human treatment, the compounds provided herein may be .. useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.
In one embodiment, the disclosure provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions implicated by KRAS G12D, G12V, G12A, G12S or mutation (e.g., cancer). The cancer types are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA data sets; " For example, the table shows that 32.4% of subjects with pancreatic cancer have a cancer wherein one or more cells express KRAS G12D
mutant protein. Accordingly, the compounds provided herein, which bind to KRASG12D
(see Section entitled "Biological Evaluation" below) are useful for treatment of subjects having a cancer, including, but not limited to the cancers listed in the table below.
Cancer Type Alteration Frequency Pancreatic Adenocarcinoma (PAAD) 32.4 Colon Adenocarcinoma (COAD) 12.25 Rectal adenocarcinoma (READ) 8.03
- 95 -Uterine corpus endometrial carcinoma 6.04 (UCEC) Lung Adenocarcinoma (LUAD) 3.53 Plasma Cell Tumors 2.92 Stomach Adenocarcinoma (STAD) 2.27 Bladder urothelial carcinoma (BLCA) 1.46 Cervical Squamous carcinoma (CESC) 1.38 Kidney Adenocarcinoma 1.07 Thymic Cancer 0.81 Myeloid Leukemia (LAML) 0.69 Liver Hepatocellular Carcinoma (LIHC) 0.55 Glioblastoma multiforme (GBM) 0.51 Skin Cutaneous Melanoma (SKCM) 0.43 Bladder Cancer 0.4 Prostate Adenocarcinoma (PRAD) 0.2 Breast Invasive Carcinoma (BRCA) 0.1 Provided herein as embodiment 325 is a compound according to any one of embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 323 for use in treating cancer.
Provided herein as Embodiment 326 is a compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 for use in treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G125 or G12C mutant protein.
Provided herein as Embodiment 327 is the compound or pharmaceutical composition for use of Embodiment 325 or 326, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
Provided herein as Embodiment 328 is a use of the compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical
- 96 -composition according to Embodiment 323 in the preparation of a medicament for treating cancer.
Provided herein as Embodiment 329 is a use of the compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C
mutant protein.
Provided herein as Embodiment 330 is the use according to Embodiment 328 or 329, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
Provided herein as Embodiment 331 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof.
Provided herein as Embodiment 332 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
Provided herein as Embodiment 333 is the method according to Embodiment 331 or 332, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
- 97 -Provided herein as Embodiment 334 is the method according to Embodiment 332 or 333, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
Provided herein as Embodiment 335 is the method according to Embodiment 334, wherein the cancer is non-small cell lung cancer.
Provided herein as Embodiment 336 is the method according to Embodiment 334, wherein the cancer is colorectal cancer.
Provided herein as Embodiment 337 is the method according to Embodiment 334, wherein the cancer is pancreatic cancer.
Provided herein as Embodiment 338 is the method according to anyone of Embodiments 331-337, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V, G12A, G12S or G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
Combination Therapy The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect. See, e.g., U.S. Patent No.
10,519,146 B2, issued December 31, 2019; specifically, the sections from column 201 (line 37) to column 212 (line 46) and column 219 (line 64) to column 220 (line 39), which are herewith incorporated by reference.
Provided herein as Embodiment 339 is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB
- 98 -family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR
inhibitor, PD-1 inhibitor, PD-Li inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent.
In one embodiment, the second compound is administered as a pharmaceutically acceptable salt. In another embodiment the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Aurora Kinase A Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A
inhibitor.
Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1- [(3 -chloro-2-fluorophenyl)methyl] -44[3 -fluoro-64(5 -methy1-1H-pyrazol-3-yl)aminolpyridin-2-yllmethy11-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-l-y1)-N-(5 -methyl-1H-pyrazol-3 -y1)-24(E)-2-phenylethenyllpyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylpheny1)-3,8-dimethyl-N-(1-methylpiperidin-4-y1)-9H-.. pyrido[2,3-blindole-7-carboxamide), TT-00420 (4-[9-(2-chloropheny1)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4Ø03,71tetradeca-1(14),3,6,8,10,12-hexaen-13-yllmorpholine), AMG 900 (N-[443-(2-aminopyrimidin-4-yl)pyridin-2-ylloxypheny11-4-(4-methylthiophen-2-yl)phthalazin-l-amine), MLN8054 (44 [9-chloro-7-(2,6-difluoropheny1)-5H-pyrimido [5,4-d][2]benzazepin-2-yllaminolbenzoic acid), PF-03814735 (N424(1R,8S)-44[4-(cyclobutylamino)-5-(trifluoromethyppyrimidin-2-yllamino1-11-azatricyclo[6.2.1.02,71undeca-2(7),3,5-trien-11-y11-2-oxoethyllacetamide), SNS-314 (143-chloropheny1)-34542-(thieno[3,2-dlpyrimidin-4-ylamino)ethy11-1,3-thiazol-2-yllurea), CYC116 (4-methyl-542-(4-morpholin-4-ylanilino)pyrimidin-4-y11-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.
AKT Inhibitors
- 99 -Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.
Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (24441-aminocyclobutyl)pheny11-3-phenylimidazo[1,2-blpyridazine-6-carboxamide), ARQ
092 (3-[3-[4-(1-aminocyclobutyl)pheny11-5-phenylimidazo [4,5-blpyridin-2-yllpyridin-2-amine), MK2206 (8-p-(1-aminocyclobutyl)pheny11-9-pheny1-2H41,2,41triazolo[3,4-f][1,61naphthyridin-3-one), SR13668 (indolo[2,3-blcarbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzy1-74(2-methylphenyl)methyll-2,5,7,11-tetrazatricyclo[7.4Ø02,61trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropy1)-N-R1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyll-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.
Ar2inase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.
Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.
CDK4/6 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4/6 inhibitor.
The term "CDK 4/6" as used herein refers to cyclin dependent kinases ("CDK") 4 and 6, which are members of the mammalian serine/threonine protein kinases.
The term "CDK 4/6 inhibitor" as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and/or 6.
- 100 -Exemplary CDK 4/6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-((pyrido[2,3-dlpyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopenty11-24[1-(methylsulfony1)-4-piperidinyllamino]).
In one embodiment, the CDK4/6 inhibitor is palbociclib.
ErbB Family Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.
The term "ErbB family" as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).
The term "ErbB family inhibitor" as used herein refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family. The modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.
In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti-EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.
In another embodiment the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.
In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).
In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR
antibody and anti-HER2 antibody.
- 101 -In one embodiment, the ErbB family inhibitor is an irreversible inhibitor.
Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino1-743-methy1-3-(4-methyl-1-piperaziny1)-1-butyn-1-y1]-6-quinazolinyll-2-propenamide)), PF 6274484 ((N44-[(3-chloro-4-fluorophenyl)aminol-7-methoxy-6-quinazoliny11-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxylanilino1-3-cyano-7-ethoxyquinolin-6-y11-4-(dimethylamino)but-2-enamide).
In one embodiment, the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.
In one embodiment, the ErbB family inhibitor is a reversible inhibitor.
Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-43-chloro-4-(3-(trifluorome thyl)phenoxy)phenyl)amino)-5H-pyrrolo [3 ,2-d] pyrimidin-5 -yl)e thyl)-3 -hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)pheny1)-N-(1-phenylethyl)-7H-pyrrolo[2,3-dlpyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethy144-[[14(3-fluorophenyl)methyll-1H-indazol-5-yllamino1-5-methylpyrrolop,1-f][1,2,41triazin-6-y11-carbamate), and GW 583340 (N43-chloro-4-[(3-fluorophenyl)methoxylpheny11-6-[2-[(2-methylsulfonylethylamino)methy11-1,3-thiazol-4-yllquinazolin-4-amine).
In one embodiment, the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.
ERK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.
Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[24[2-[(2-methoxy-5-methylpyridin-4-yl)amino1-5-(trifluoromethyppyrimidin-4-yllaminol-5-methylphenyllprop-2-enamide), LY3214996 (6,6-dimethy1-242-[(2-methylpyrazol-3-y0aminolpyrimidin-4-yll-5-(2-
- 102 -morpholin-4-ylethypthieno[2,3-clpyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridiny1)-7H-pyrazolo[4,3-glquinazolin-7-one), ASTX029, LTT462, and JSI-1187.
FAK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.
Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (24[5-chloro-2-[(5-methy1-2-propan-2-ylpyrazol-3-y1)aminolpyridin-4-yllaminol-N-methoxybenzamide), PF-00562271 (N-methyl-N43-[[[2-[(2-oxo-1,3-dihydroindo1-5-yl)amino1-5-(trifluoromethyppyrimidin-4-yllaminolmethyllpyridin-2-yllmethanesulfonamide), VS-4718 (24[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyppyridin-4-yllaminol-N-methylbenzamide), and APG-2449.
FGFR Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.
Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASPS 878 (2444[54(2,6-difluoro-3,5-dimethoxyphenyOmethoxylpyrimidin-2-yllaminolpyrazol-1-yllethanol), AZD4547 (N-[542-(3,5-dimethoxyphenypethy11-1H-pyrazol-3-y11-4-[(3S,5R)-3,5-dimethylpiperazin-1-yllbenzamide), debio 1347 (115-amino-1-(2-methy1-3H-benzimidazol-5-yl)pyrazol-4-y11-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N424[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylaminolpyrimidin-4-yllamino1-5-(4-ethylpiperazin-l-yl)phenyllprop-2-enamide), ICP-105, CPL304110, FIMPL-453, and HGS1036.
Glutaminase Inhibitors
- 103 -Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.
Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.
IGF-1R Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.
Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1444(5-cyclopropyl-1H-pyrazol-3-yl)aminolpyrrolo p, 1-f]
[1,2,41triazin-2-yll -N-(6-fluoropyridin-3-y1)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N45 -[442-hydroxyacetyl)piperazin-l-yll methyl] -2- RE)-2 -(1H-indazol-3-ypethenyll phenyl] -3 -methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.
KIF18A Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.
Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020/0239441, WO 2020/132649, WO
2020/132651, and WO 2020/132653, each of which is herewith incorporated by reference in its entirety.
MCL-1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.
- 104 -Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethy1-22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno-10H,20H-pyrazolo [4,3-1] [2,15,22,18,191benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((aR)-a-[[(5S)-543-Chloro-2-methy1-442-(4-methy1-1-piperazinypethoxylphenyll-6-(4-fluorophenyl)thieno[2,3-dlpyrimidin-4-ylloxyl-2-[[2-(2-methoxyphenyl)-4-pyrimidinyllmethoxylbenzenepropanoic acid), and ABBV-467.
In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.
MEK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is MEK inhibitor.
Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethy1-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-alpyridine-6-carboxamide), R04987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-54(3-oxooxazinan-2-yl)methyllbenzamide), TAK-733 (34(2R)-2,3-dihydroxypropyll-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-dlpyrimidine-4,7-dione), PD0325901 (N4(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxypheny1)-4H-chromen-4-one), PD334581 (N-[543,4-Difluoro-2-[(2-fluoro-4-iodophenyl)aminolpheny11-1,3,4-oxadiazol-2-y11-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.
In one embodiment, the MEK inhibitor is trametinib.
- 105 -mTOR Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.
Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (1-(4-(4-propionylpiperazin-1-y1)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-y1)benzo[h][1,61naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethy1-3-(4-(4-(3-.. methylmorpholino)-7-(oxetan-3-y1)-5,6,7,8-tetrahydropyrido[3,4-dlpyrimidin-yl)phenyOurea), and VS-5584 (5B2343, (5-(8-methy1-2-rnorpholin-4-y1-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).
In one embodiment, the mTOR inhibitor is everolimus.
PD-1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.
Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS
001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibody as described in US 10,640,504 B2 (the "Anti-PD-1 Antibody A,"
column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference.
In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment the PD-1 inhibitor is the Anti-PD-1 Antibody A.
PD-Li Inhibitors
- 106 -Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-Li inhibitor.
Exemplary PD-Li inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.
In one embodiment, the PD-Li inhibitor is atezolizumab.
PI3K Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.
Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acalisib, CUDC-907 (N-hydroxy-24[2-(6-methoxypyridin-3-y1)-4-morpholin-4-ylthieno[3,2-dlpyrimidin-6-yllmethyl-methylaminolpyrimidine-5-carboxamide), ME-401 (N-[2-methy1-1-[2-(1-methylpiperidin-4-yOphenyllpropan-2-y11-4-(2-methylsulfonylbenzimidazol-1-y1)-morpholin-4-y1-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-R1S)-1-[8-[2-(1-methylpyrazol-4-ypethynyll -1-oxo-2-phenylisoquinolin-3-yllethyllpyrazolo [1,5 -alpyrimidine carboxamide), SF1126 425)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-24[4-oxo-44[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yllmethoxylbutanoyllaminolpentanoyllaminolacetyllaminolpropanoyllamino1-3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-y11-4-methylbenzenesulfonamide), GSK1059615 45Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene1-1,3-thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-ypethyll-7H-purin-6-amine).
Raf Kinase Inhibitors
- 107 -Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.
The term "RAF kinase" as used herein refers to a member of a mammalian serine/threonine kinases composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C-Raf/B-Raf heterodimers.
The term "Raf kinase inhibitor" as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases, or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.
In one embodiment, the Raf kinase inhibitor includes, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-y1)-3a,7a-dihydro-1H-pyrrolo[2,3-blpyridine-3-carbony1)-2,4-difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methy1-5,-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin1-5-y1)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-y1)-4-methylpheny1)-2-(trifluoromethypisonicotinamide), LY3009120 (1-(3,3-dimethylbuty1)-3-(2-fluoro-4-methy1-5-(7-methy1-2-(methylamino)pyrido[2,3-dlpyrimidin-6-yOphenyOurea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)pheny1)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-ypisoxazol-3-yOurea), (1-(3-(tert-buty1)-1-pheny1-1H-pyrazol-5-y1)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-blpyrazin-8-ypoxy)phenyOurea), and R05126766 (N-[3-fluoro-44[4-methy1-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yllmethy11-2-pyridinyll-N-methyl-sulfamide).
In one embodiment, the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib.
SHP2 Inhibitors
- 108 -Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.
Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-y1)-3-(2,3-dichlorophenyOpyrazin-2-amine dihydrochloride), RMC-4550 ([34(3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51decan-8-y11-6-(2,3-dichloropheny1)-5-methylpyrazin-2-yllmethanol), TN0155, (3S,4S)-846-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-y11-3-methy1-2-oxa-8-azaspiro[4.51decan-4-amine), and RMC-4630 (Revolution Medicine). In one embodiment, the SHP inhibitor for use in the methods provided herein is RMC-4630 (Revolution Medicine).
In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.51dec-8-y11-6-(2,3-dichloropheny1)-5-methy1-2-pyrazinemethanol (CAS 2172651-08-8), 3-R3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-64(2,3-dichlorophenyl)thio1-5-methy1-2-pyrazinemethanol (CAS 2172652-13-8), 3-R3S,45)-4-amino-3-methyl-2-oxa-8-azaspiro[4.51dec-8-y11-64[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyllthiol-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 64(2-amino-3-chloro-4-pyridinyl)thio1-R3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-5-methy1-2-pyrazinemethanol (CAS 2172652-48-9).
In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 145-(2,3-dichloropheny1)-6-methylimidazo[1,5-alpyrazin-8-y11-4-methy1-4-piperidinamine (CAS 2240981-75-1), (1R)-845-(2,3-dichloropheny1)-6-methylimidazo[1,5-alpyrazin-8-y11-8-azaspiro[4.51decan-1-amine (CAS
2240981-78-4), (3S,4S)-847-(2,3-dichloropheny1)-6-methylpyrazolo[1,5-alpyrazin-4-y11-3-methy1-2-oxa-8-azaspiro[4.51decan-4-amine (CAS 2240982-45-8), (3S,4S)-8474(2-amino-3-chloro-4-pyridinyl)thiolpyrazolo[1,5-alpyrazin-4-y11-3-methy1-2-oxa-8-azaspiro[4.51decan-4-amine (CAS 2240982-57-2), 44(3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-7-(2,3-dichloropheny1)-6-methyl-pyrazolo[1,5-alpyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyOthio1-44(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.51dec-8-y11-6-methyl-pyrazolo[1,5-alpyrazine-2-methanol (CAS
2240982-73-2),
- 109 -and (3S,4S)-8-[74(2-amino-3-chloro-4-pyridinyl)thio1-6-methylpyrazolo[1,5-alpyrazin-4-y11-3-methy1-2-oxa-8-azaspiro[4.51decan-4-amine (CAS 2240982-77-6).
In one embodiment, the SHP inhibitor for use in the methods provided herein is (1R)-845-(2,3-dichloropheny1)-6-methylimidazo[1,5-alpyrazin-8-y11-8-azaspiro[4.51decan-1-amine (CAS 2240981-78-4).
In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 34(1R)-1-amino-8-azaspiro[4.51dec-8-y11-6-(2,3-dichloropheny1)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.51dec-8-y11-64(2,3-dichlorophenyl)thio1-5-hydroxy-2-pyridinemethanol (CAS
2238840-56-5), 54(1R)-1-amino-8-azaspiro[4.51dec-8-y11-2-(2,3-dichloropheny1)-3-pyridinol (CAS 2238840-58-7), 34(1R)-1-amino-8-azaspiro[4.51dec-8-y11-6-(2,3-dichloropheny1)-5-methy1-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichloropheny1)-5-methyl-3-pyridiny11-8-azaspiro[4.51decan-1-amine (CAS 2238840-62-3), 34(1R)-1-amino-8-azaspiro[4.51dec-8-y11-64(2,3-dichlorophenyOthio1-5-methy1-2-pyridinemethanol (CAS
2238840-63-4), (1R)-8464(2,3-dichlorophenyl)thio1-5-methy1-3-pyridiny11-8-azaspiro[4.51decan-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidiny1)-2-[(2,3-dichlorophenyl)thio1-3-pyridinol (CAS 2238840-65-6), 54(1R)-1-amino-8-azaspiro[4.51dec-8-y11-24(2,3-dichlorophenyl)thio1-3-pyridinol (CAS 2238840-66-7), 64(2-amino-3-chloro-4-pyridinyl)thio1-3-[(3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidiny1)-6-(2,3-dichloropheny1)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-R3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-6-(2,3-dichloropheny1)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 64(2-amino-3-chloro-4-pyridinyl)thio1-3-R3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-5-methy1-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidiny1)-6-(2,3-dichloropheny1)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 64(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidiny1)-2-pyridinemethanol (CAS 2238840-72-5), 54(2-amino-3-chloro-4-pyridinyl)thio1-24(3S,4S)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-6-methy1-3-pyridinemethanol (CAS 2238840-73-6), 2-R3S,4S)-4-amino-3-methy1-2-oxa-.. azaspiro[4.51dec-8-y11-5-(2,3-dichloropheny1)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 34(3S,45)-4-amino-3-methy1-2-oxa-8-azaspiro[4.51dec-8-y11-6-(2,3-dichloropheny1)-
- 110 -5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8), and 2-[(2-amino-3-chloro-4-pyridyl)sulfany11-5-[(3S,4S)-4-amino-3- methy1-2-oxa-8-azaspiro[4.51decan-8-y11-6-(hydroxymethyppyridin-3-01.
In one embodiment, the SHP inhibitor for use in the methods provided herein is [(1R)-1-amino-8-azaspiro [4 .5] dec-8-yll -6- [(2,3-dichlorophenyOthio] -5 -hydroxy-2-pyridinemethanol (CAS 2238840-56-5).
In one embodiment, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020/017517 Al, US 2020/017511 Al, or WO
2019/075265 Al, each of which is herewith incorporated by reference in its entirety.
SOS1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.
Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-143-amino-5-(trifluoromethyl)phenyllethy11-7-methoxy-2-methy1-6-[(3S)-oxolan-3-ylloxyquinazolin-4-amine), and BI 1701963.
Src Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.
The term "Src kinase" as used herein refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA
subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily.
The term "Src kinase inhibitor" as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases.
Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzy1-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-
- 111 -dimethy1-2-oxo-3-((4,5,6,7-tetrahydro-1H-indo1-2-y1)methylene)indoline-5-sulfonamide), PP
1 (1-(tert-butyl)-3-(p-toly1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylpheny1(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzy1-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yOacetamide).
In one embodiment, the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.
Chemotherapeutic Agents Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agent.
Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.
Definitions The following definitions are provided to assist in understanding the scope of this disclosure.
Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.
As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If
- 112 -the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
Stereoisomers The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the instant disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.
If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
The term "stereoisomer" or "stereoisomerically pure" compound as used herein refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of the compound. A typical stereoisomerically pure .. compound comprises greater than about 80% by weight of one stereoisomer of the compound
- 113 -and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.
This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers.
These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents.
Further, this disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein and one or more other active agents disclosed herein. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen etal., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
Tautomers As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula.
Accordingly, the scope of the instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein.
- 114 -Isotopically-Labelled Compounds Further, the scope of the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, such as the compounds of Formula I, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2H and 3I-1, carbon, such as "C, 13C
and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 1231 and 1251, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S. Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances.
Substitution with positron emitting isotopes, such as HC, 18F, 150 and '3N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy.
Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
Solvates As discussed above, the compounds disclosed herein and the stereoisomers, tautomers, and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.
The term "solvate" as used herein refers to a molecular complex comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a
- 115 -stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a "hydrate."
Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing.
Miscellaneous Definitions This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.
The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term "aryl" as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted with 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-O-, aryl-O-, heteroary1-0-, amino, thiol, alkyl-S-, aryl-S--nitro, cyano, carboxy, alkyl-O-C(0)--, carbamoyl, alkyl-S(0)-, sulfonyl, sulfonamido, phenyl, and heterocycloalkyl.
The terms "Ci_4alkyl," and "Ci_6alkyl" as used herein refer to a straight or branched chain hydrocarbon containing from 1 to 4, and 1 to 6 carbon atoms, respectively.
Representative examples of C1_4alkyl or C16 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
The terms "C1_4alkylene" and "C1_6alkylene" refer to a straight or branched divalent alkyl group as defined herein containing 1 to 4, and 1 to 6 carbon atoms, respectively.
Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene and the like.
The term "C2_4alkenyl" as used herein refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include
- 116 -both straight and branched moieties. Representative examples of C2_4alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.
The term "C2_4alkynyl" as used herein refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon triple bond The lerm includes both straight and branched moieties. Representative examples of C3..6alkynyl include, but are not limited to, etbynyi, 1 -propynyl, 2-propynyl, 2-butynyl and 3-butynyl.
The term "Ci_4alkoxy" or "Ci_6alkoxy" as used herein refers to ¨01e, wherein R#
represents a C1_4alkyl group or Ci_6alkyl group, respectively, as defined herein.
Representative examples of C1_4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. Representative examples of C1_6alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.
The term "C3_8cycloalkyl" as used herein refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 8 carbons. Representative examples of C3_8cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.
The term "deutero" as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with deuterium ("D" or "2H"). For example, the term "Ci_4deuteroalkyl" refers to a Ci_4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D.
Representative examples of Ci_4deuteroalkyl include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).
The term "halogen" as used herein refers to ¨F, -CI, -Br, or -I.
The term "halo" as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is independently selected at each occurrence.
For example, the term "C1_4haloalkyl" refers to a C1_4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of Ci_ 4ha10a1ky1 include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFC1, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3).
As used herein, the term "heteroaryl" refers to a 5-20 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, 0 and S. In certain preferred aspects, the heteroaryl is a 5-10 membered ring system (e.g., 5-7
- 117 -membered monocycle, an 8-10 membered bicycle or a 11-14 membered tricycle) or a 5-7 membered ring system. Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2-or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3-or 5-1,2,4-triazolyl, 4-or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, and 5-pyrimidinyl. Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or 8-benzimidazoly1 and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-indolyl.
The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloalkyl rings.
As used herein, the term "heterocycle," "heterocycloalkyl" or "heterocyclo"
refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14-or 15-membered tricyclic ring system and contains at least one heteroatom selected from 0, S
and N, where the N and S can also optionally be oxidized to various oxidation states. The heterocyclic group can be attached at a heteroatom or a carbon atom. The heterocycloalkyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran, dihydrofuran, 1, 4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and the like.
The term "pharmaceutically acceptable" as used herein refers to generally recognized for use in subjects, particularly in humans.
The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) 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 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,
- 118 -benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like. Additional examples of such salts can be found in Berge etal., I
Pharm. Sci.
66(1):1-19 (1977). See also Stahl etal., Pharmaceutical Salts: Properties, Selection, and Use, 211' Revised Edition (2011).
The term "pharmaceutically acceptable excipient" as used herein refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
The term "subject" as used herein refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment the subject is a human.
The term "therapeutically effective amount" as used herein refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, a system, or subject that is being sought by a researcher, veterinarian, medical doctor or other clinician.
GENERAL SYNTHETIC PROCEDURES
The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.
- 119 -Generally, the compounds of Formula I can be synthesized according to the following schemes. Any variables used in the following schemes are the variables as defined for Formula I, unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd.
or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting material may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as, solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein.
X ROH OR OR
Or A I A I RI
X N X X N X NI X
A

(12x)p¨r X11 )m (Rx)p¨C X11 )m OR OH n W-) n HI
N N N N N N
RI I
N R3 N R3 s N R3 Scheme!
Compounds of Formula (I) can be prepared according to Scheme!. In step A, compound (I-1) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig's base, or metal alkoxide, such as potassium tert-butoxide, in a solvent such as 1,4-dioxane to give compound (I-2). In step B, compound (I-2) undergoes SNAr reaction with a nucleophile haying the formula R1--L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig's base, to give compound (I-3). In step C, compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as
- 120 -cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (I-4) is treated with a suitable set of reagents, such as Pd/C with H2 to remove the alkyl group R, giving compound (I-5). In Step E, compound (I-5) is treated with an optionally substituted cyclic amine in the presence of coupling reagent such as HATU, and a base such as Hunig's base, in a solvent such as DMA to give compounds of Formula (I). In some cases, the species R3 will contain protecting group(s), which can be removed in step D or after step E in the synthetic sequence.
's 's N N NaSMe N N R1-L-1-1 N N R3-M

X N A
X XA N X VLN X

X (RA x)p X /1 ) m (Rx)pl n W"
vv) N N
HI N N
R1 I Ri L'N R3 L N R3 Scheme II
Compounds of Formula (I) can also be prepared according to Scheme II. In step A, compound (I-1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (I-6). In step B, compound (I-6) undergoes SNAr reaction with a nucleophile having the formula R1-L-H in a solvent such as acetonitrile in the presence of a base such as Hunig's base to give compound (I-7). In .. step C, compound (I-7) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-8). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (I-8) is coupled with an optionally substituted cyclic amine in the presence of a
- 121 -palladium catalyst, such as Pd(PPh3)4, a copper catalyst, such as CuTC, in a solvent such as 1,4-dioxane, to give compounds of formula (I). In some cases, the species R3 will contain protecting group(s), which can be removed after step D in the synthetic sequence.
' (Rx)pl m )rn n( CI
nµ
N N S02C12 N N NLI,N
121, I 121, Ø.4 I N R3 N R3 A

Scheme III
Compounds of Formula (I) can also be prepared according to Scheme III. In step A, compound (1-8) is treated with sulfuryl chloride in a solvent such as dichloromethane to give compound (1-9). In step B, compound (1-9) undergoes SNAr reaction with an optionally substituted cyclic amine in a solvent such as acetonitrile in the presence of a base such as Hunig's base to give compounds of formula (I). In some cases, the species R3 will contain protecting group(s), which can be removed after step B
in the synthetic sequence.
- 122 -x X
(Rx)pl x (Rx)pl (Rx)p )¨x.(1)m n( 4W-tit d n W
N N HI NY 'N R1-L-H N N
I I

X N X A X N X L NI
X

X
(Rx)pl im n W.

-)0.- R1, I
L N

Scheme IV
Compounds of Formula (I) can also be prepared according to Scheme IV. In step A, compound (1) undergoes SNAr reaction with an optionally substituted cyclic amine in a solvent such as dichloromethane and in the presence of a base such as Hunig's base to give compound (I-10). In step B, compound (I-10) undergoes SNAr reaction with a nucleophile having the formula le-L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig's base to give compound (I-11). In step C, compound (I-11) is coupled with an organometallic reagent or a boronic acid (ester) to provide compounds of formula (I). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In some cases, the species le will contain protecting group(s), which can be removed after step C
in the synthetic sequence.
EXAMPLES
This section provides specific examples of compounds of Formula I and methods of making the same.
- 123 -List of Abbreviations Table 1 Ac acetyl AcC1 acetyl chloride AcOH acetic acid aq or aq. aqueous Bn benzyl B2pin2 bis(pinacolato)diboron BOC or Boc tert-butyloxycarbonyl cataCXium A Pd G3 mesylate[(di(1-adamanty1)-n-butylphosphine)-2-(2'-amino-1,11-biphenyOlpalladium(II) Cbz benzyloxycarbonyl CbzCl benzyl chloroformate CDI carbonyldiimidazole COD or cod 1,5-cyclooctadiene CuTC copper(I) thiophene-2-carboxylate DABCO I A-diazabicyclo [2.2 . Thc-tane DBU I .8-di azabi cyclo [5 .4. Olundee- 7-ene DCM dichloromethane DMA /V,N-dimethylacetamide DMF /V,N-dimethylformamide DMSO dimethyl sulfoxide Dppf, DPPF or dppf 1,1' -bis(diphenylphosphino)ferrocene Dtbbpy 4,4'-di-tert-buty1-2,2'-dipyridyl eq or eq. or equiv. equivalent ESI or ES electrospray ionization Et ethyl Et0Ac ethyl acetate gram(s) hour(s) 1-[bis(dimethylamino)methylene]-1H-1,2,3-HATU
triazolo[4,5-blpyridinium 3-oxide hexafluorophosphate HBpin 4,4,5,5-tetramethy1-1,3,2-dioxaborolane HMPA hexamethylphosphoramide HOAc acetic acid HPLC high pressure liquid chromatography iPr iso-propyl iPr2NEt or DIPEA N-ethyl diisopropylamine (1-11.inig's base) KOAc potassium acetate LC MS, LCMS, LC-MSli or LC/MS quid chromatography mass spectroscopy LHMDS or LiHMDS lithium hexamethyldisilazide
- 124 -m/z mass divided by charge Me methyl MeCN acetonitrile Me OH methanol Mg milligrams Min minutes mL milliliters MOM methoxymethyl MOMC1 methoxymethyl chloride MS mass spectra NMR nuclear magnetic resonance PC Pd G2 chloroRtricyclohexylphosphine)-2-(2 y3 /-aminobiphenyOlpalladium(II) Pd(dppf)C12.DCM, bis(diphenylphosphino)ferroceneldichloropalladium(II), Pd(dppf)C12 complex with dichloromethane [1,1'-bis(di-tert-Pd(dtbpf)C12 butylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Ph phenyl PhMe toluene Pin pinacolato Piv pivaloyl PivC1 pivaloyl chloride PMB 4-methoxybenzyl Rbf round-bottom flask RP-HPLC reverse phase high pressure liquid chromatography RT or rt or r.t. room temperature sat. or satd. saturated SFC supercritical fluid chromatography TBAF tetra-n-butylammonium fluoride TBDPS tert-butyldiphenylsilyl TBDPSC1 tert-butyldiphenylsilyl chloride TB S tert-butyldimethylsilyl TB SC1 tert-butyldimethylsilyl chloride tBu tert-butyl TC thiophene-2-carboxylate TEA or Et3N triethylamine Tf trifluoromethylsulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TIPSC1 triisopropylsilyl chloride UV ultraviolet
- 125 -XPh 2-dicyclohexylphosphino-2',4',6'-triisopropy1-1,1'-os biphenyl X phos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-bipheny1)[2-(2'-amino-1,1'-biphenyl)palladium(II) General Analytical and Purification Methods Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.
Chromatography: Unless otherwise indicated, crude product-containing residues were purified by passing the crude material or concentrate through either a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and eluting the product off the column with a solvent gradient as indicated.
Preparative HPLC Method: Where indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument included:
eluting at 45 mL/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.
Proton NMR Spectra: Unless otherwise indicated, all 'El NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. All observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some 'El signals may be missing due to exchange with D from Me0D, or due to signal suppression.
Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and/or exemplary compounds are reported as mass/charge (m/z), having an [M+H]+ molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC/MS
system.
- 126 -Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art.
Preparation of Intermediates 05,6-Difluoro-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)naphthalen-2-ypoxy)triisopropylsilane (Intermediate A) OEt (nBu)3Sn' Mel, DBU 1 F 0 PdC12(PPh3)2, PhCF3 KOtBu F OH
F so Br F Br F
CO2H PhMe CO2Me 2 HCI RIP CO2Me THF OH
Step 1 Step 2 Step 3 0õ0 TIPSCI, DIPEA F OH Tf20, DIPEA F OTf B2pin2, KOAc, pdC12(dPPf) F B
DCM _________________ F sigh DCM ________________________________ F
PhMe (crSij Step 4 glir 0 r Step 5 0 r Step 6 Intermediate A
Step 1: Methyl 2-(2-bromo-3,4-difluorophenyl)acetate. To a 100-mL round-bottomed flask was added 2-(2-bromo-3,4-difluorophenyl)acetic acid (2.00 g, 7.97 mmol) and DBU (1.21 g, 1.20 mL, 7.97 mmol), and toluene (40 mL). To the mixture was added MeI
(2.26 g, 1.0 mL, 15.93 mmol) and the mixture was stirred at rt for 4 h. Upon completion, the reaction was diluted with water and extracted with Et0Ac. The organic layer was dried, concentrated, and chromatographed with 0-50% Et0Ac in heptane to give methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol, 77 % yield) as a colorless oil.
m/z (EST): 265.0 (M+H)+.
Step 2: Methyl 2-(2-acetyl-3,4-difluorophenyl)acetate. A microwave vial was charged with methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol), trifluorotoluene (15 mL), tributy1(1-ethoxyvinyl)stannane (4.41 g, 12.22 mmol), and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.86 g, 1.22 mmol). The vial was purged with nitrogen for 2 min, sealed, and placed in a microwave reactor for 12 h at 150 C. Upon completion, the mixture was filtered through a celite / silica plug and concentrated. The resulting yellow oil was disolved in THF (10 mL) and 5 mL of 5 N HC1 were added. The reaction was stirred at rt for 30 min. Upon completion, the reaction was poured slowly into a seperatory funnel containing saturated NaHCO3. The mixture was extracted with Et0Ac,
- 127 -dried, concentrated and chromatographed with 0-30% Et0Ac in heptane to give methyl 2-(2-acety1-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol, 87 % yield) as colorless oil. m/z (ESI):
229.1 (M+H)+.
Step 3: 7,8-Difluoronaphthalene-1,3-diol. To a 250 mL round-bottomed flask was added methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol), KOtBu (1.79 g, 15.91 mmol) and THF (40 mL). The flask was capped and placed in a preheated aluminum block kept at 80 C for 3 h. Upon completion, the reaction was diluted with 1 M HC1, extracted with DCM, and dried to give 7,8-difluoronaphthalene-1,3-diol (1.04 g, 5.30 mmol, 100 % yield) as red oil. m/z (ESI): 197.0 (M+H)+.
Step 4: 7,8-Difluoro-3-((triisopropylsilyDoxy)naphthalen-1-ol. To a 100-mL
round-bottomed flask was added 7,8-difluoronaphthalene-1,3-diol (0.75 g, 3.82 mmol), DIPEA (2.00 mL, 11.47 mmol) and DCM (38 mL). The solution was cooled to 0 C
and TIPS-C1 (0.66 g, 0.73 mL, 3.44 mmol) was added. The reaction was allowed to warm to rt.
Upon completion, the reaction was concentrated and chromatographed with 0-30%
Et0Ac in heptanes. Isomers separated with silica gel column with 0-30% Et0Ac in heptane to give 7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-1-ol (0.88 g, 2.51 mmol, 66 %
yield) (first eluting isomer) as the major product and 5,6-difluoro-4-((triisopropylsilyl)oxy)naphthalen-2-ol (0.18 g, 0.50 mmol, 13 % yield) (second eluting isomer) as the minor product. m/z (ESI):
353.2 (M+H)+.
Step 5: 7,8-Difluoro-3-((triisopropylsilyDoxy)naphthalen-1-y1 trifluoromethanesulfonate. To a 100-mL round-bottomed flask was added 7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-1-ol (0.88 g, 2.50 mmol), DIPEA (1.31 mL, 7.51 mmol) and DCM (25 mL). The solution was cooled to 0 C and Tf20 (1 M in DCM, 2.76 mL, 2.76 mmol) was added. The reaction was allowed to warm to rt and stir for 1 h. Upon completion, the reaction was poured into a seperatory funnel containing saturated NaHCO3 and extracted with DCM. The organic layer was dried and concentrated to give 7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-1-yltrifluoromethanesulfonate (1.21 mg, 2.51 mmol, 100 % yield) as orange oil which was used in the following step without further purification.
m/z (ESI): 485.1 (M+H)+.
Step 6: ((5,6-Difluoro-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Anaphthalen-2-yDoxy)triisopropylsilane. A 100-mL round-bottomed flask was charged
- 128 -with 7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-l-y1 trifluoromethanesulfonate (1.21 g, 2.50 mmol), bis(pinacalato)diboron (1.27 g, 4.99 mmol), potassium acetate (0.86 g, 8.74 mmol), 1, l'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.37 g, 0.499 mmol) and toluene (25 mL). The reaction was purged with nitrogen for 5 minutes and then stirred at 80 C for 12 h. Upon completion, the reaction was concentrated and chromatographed with a gradient of 0-40% Et0Ac in hexanes to give ((5,6-difluoro-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)naphthalen-2-y0oxy)triisopropylsilane (0.97 g, 2.09 mmol, 84 % yield).
m/z (ESI): 463.3 (M+H)+.
2-(8-Ethy1-7-fluoronaphthalen-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate B) TIPS ________________ = Br TIPS TIPS

RuCl2(p-cymene)2 Ply-Cl, NEt3 >A0 I I
OH AcOK OH DMAP
1,4-dioxane DCM
Step 1 Step 2 1) CsF, DMF
2) 10% Pd/C, H2 B2Pin2, AcOK
0õ0 Me0H OH Tf20, NEt3 OTf Pd(clopf)C12 3) KOH, Me0H DCM
1,4-dioxane Step 3 Step 4 Step 5 Intermediate B
Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol. A pressure relief vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-1-naphthol (1.00 g, 6.17 mmol, Enamine), dichloro(p-cymene)ruthenium(II)dimer (0.38 g, 0.62 mmol, Alfa Aesar) and then purged with nitrogen for 5 min. The solids were then suspended in 1,4-dioxane (12 mL) and (bromoethynyOtriisopropylsilane (1.77 g, 1.63 mL, 6.78 mmol, Enamine) was added. The reaction was then stirred at 110 C for 18 h and subsequently at room temperature for 2-d. Volatiles were removed in vacuo and the crude material was absorbed onto silica gel. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 0-20% Et0Ac in heptane to yield 7-fluoro-8-
- 129 -((triisopropylsilypethynyl)naphthalen-l-ol (1.90 g, 5.55 mmol, 90 % yield) as a yellow oil.
m/z (ESI, +ve ion): 343.0 (M+H)+.
Step 2: 7-Fluoro-8-((triisopropylsilyDethynyOnaphthalen-1-y1 pivalate. 7-Fluoro-8-((triisopropylsilypethynyl)naphthalen-1-ol (1.00 g, 2.92 mmol) was dissolved in dichloromethane (11 mL) and cooled to 0 C. DMAP (0.07 g, 0.58 mmol, Sigma-Aldrich Corporation) and TEA (0.89 g, 1.23 mL, 8.76 mmol, Sigma-Aldrich Corporation) were added, followed by dropwise addition of pivaloyl chloride (1.06 g, 1.08 mL, 8.76 mmol, Sigma-Aldrich Corporation). The mixture was warmed to room temperature and stirred for 45 minutes. Water (10 mL) was added and the aqueous layer extracted with DCM (2 x 10 mL).
The combined organic phase was dried over anhydrous Na2SO4. Volatiles were removed in vacuo and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-10% Et0Ac in heptane to yield 7-fluoro-8-((triisopropylsilypethynyOnaphthalen-1-ylpivalate (1.13 g, 2.65 mmol, 91 %
yield) as yellow crystalline solid. m/z (ESI, +ve ion): 427.4 (M+H)+.
Step 3: 8-Ethy1-7-fluoronaphthalen-1-ol. A scintillation vial was charged with fluoro-8-((triisopropylsilypethynyl)naphthalen-1-y1 pivalate (1.13 g, 2.65 mmol) and dissolved in DMF (12 mL). Cesium fluoride (4.02 g, 26.5 mmol, Sigma-Aldrich Corporation) was added and the mixture stirred at rt for 30 minutes. Water (100 mL) was added and the aqueous phase extracted with Et0Ac (2 x 20 mL). The combined organic layer was dried over Na2SO4 and volatiles were then removed in vacuo to yield 8-ethyny1-7-fluoronaphthalen-1-yl pivalate (0.72 g, 2.65 mmol, quantitative yield) as a crude yellow oil that was used without further purification.
8-Ethyny1-7-fluoronaphthalen-1-ylpivalate (0.72 mg, 2.65 mmol) was dissolved in Me0H (9 mL) and palladium on activated carbon (85 mg, 0.795 mmol, Sigma-Aldrich Corporation) was added. The reaction vessel was purged with H2 and then stirred under a H2 atmosphere (15 psi) at room temperature for 2 h. The mixture was filtered over celite, washed with Et0Ac until the filtrate ran clear and volatiles were removed in vacuo.
The crude material was then dissolved in Me0H (10 mL) and potassium hydroxide (0.45 g, 7.95 mmol, VWR International, LLC) was added. After stirring at room temperature for 2 h, the pH of the solution was adjusted to pH = 3 using 1 M aq. HC1. Water (20 mL) was added and the aqueous phase extracted with Et0Ac (3 x 10 mL). The combined organic layer was dried
- 130 -over Na2SO4 and volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-20% Et0Ac in heptane to yield 8-ethy1-7-fluoronaphthalen-1-ol (0.35 g, 1.84 mmol, 70% yield) over 3 steps as yellow oil. m/z (ESI, +ve ion): 191.2 (M+H)+.
Step 4: 8-Ethyl-7-fluoronaphthalen-l-y1 trifluoromethanesulfonate. 8-Ethy1-7-fluoronaphthalen-1-ol (0.35 g, 1.84 mmol) was dissolved in DCM and cooled to 0 C. TEA
(0.28 g, 0.39 mL, 2.76 mmol, Sigma-Aldrich Corporation) was added, followed by dropwise addition of a 1 M Tf20 solution (2.02 mL, 2.02 mmol, Sigma-Aldrich Corporation). The mixture was stirred at rt for 20 minutes and poured into ice water (20 mL).
The aqueous phase was extracted with DCM (2 x 10 mL), the combined organic layers were dried over Na2SO4 and volatiles were removed in vacuo. The crude mixture was purified by column chromatography on silica gel, eluting using a gradient of 0-5% Et0Ac in heptane to yield 8-ethy1-7-fluoronaphthalen-1-y1 trifluoromethanesulfonate (0.47 g, 1.47 mmol, 80 % yield) as colorless oil. 1HNMR (400 MHz, CHLOROFORM-d) 6 ppm 7.86 (dd, J=8.3, 0.9 Hz, 1 H), 7.79 (dd, J=9.4, 6.5 Hz, 1 H), 7.59 (dt, J=7.7, 0.8 Hz, 1 H), 7.44 (t, J=8.2 Hz, 1 H), 7.36 (t, J=9.4 Hz, 1 H), 3.32 (qd, J=7.5, 2.9 Hz, 2 H), 1.29 (t, J=7.4 Hz, 3 H).
Step 5: 2-(8-Ethy1-7-fluoronaphthalen-1-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane. Potassium acetate (0.43 g, 4.38 mmol, Sigma-Aldrich Corporation) was placed in a pressure relief vial and dried under vacuum. Then, 8-ethy1-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (0.47 g, 1.46 mmol), bis(pinacalato)diboron (0.74 g, 2.92 mmol, Combi-Blocks Inc.) and [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (0.11 g, 0.15 mmol, Sigma-Aldrich Corporation) were added and the mixture stirred at 90 C for 3 h and then at rt for 12 h. Volatiles were removed in vacuo and the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-15% Et0Ac in heptane to yield 2-(8-ethy1-7-fluoronaphthalen-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.50 mmol, 34% yield) as yellow wax. m/z (ESI, +ve ion): 301.0 (M+H)+.
7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate C)
- 131 -HO

BnOH
N 1\1 CI CI e 'Pr2NEt N 1\1 'Pr2NEt .. N
.. 1\1 N CI N CI CI N 0 ' Dioxan MeCN
Step 1 Step 2 13,0 cataCXium A Pd G3 N 1\1 Pd/C N 1\1 ______________ =
THE/water Et0Ac Step 3 Step 4 Intermediate C
Step 1: 4-(Benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. A 250-mL
round-bottom flask charged with activated 3A molecular sieves was added 1,4-dioxane (48 mL), DIPEA (9.22 g, 12.5 mL, 71.3 mmol), benzyl alcohol (3.86 g, 3.7 mL, 35.7 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-dlpyrimidine (6.00 g, 23.8 mmol). The mixture was stirred at 85 C for 2 h. Volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0 - 100% 3:1 Et0AciEt0H blend in heptane to yield 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-dlpyrimidine (3.30 g, 10.18 mmol, 43 %
yield). m/z (ESI): 325.9 (M+H)+.
Step 2: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-dlpyrimidine (3.30 g, 10.18 mmol) in acetonitrile (20 mL) were added 42S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.78 g, 11.20 mmol) and DIPEA (5.26 g, 7.1 mL, 40.7 mmol). The reaction was stirred at 80 C
for 1 h.
Volatiles were removed under reduced pressure and the mixture was purified by column chromatography on silica gel, eluting with 0-100% 3:1 Et0AciEt0H blend in heptane with 2% triethylamine additive to yield 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-
- 132 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidine (2.60 g, 5.82 mmol, 57 % yield). m/z (ESI): 447.0 (M+H)+.
Step 3: 4-(Benzyloxy)-7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidine (2.60 g, 5.82 mmol) and 2-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.14 g, 8.73 mmol) in tetrahydrofuran (17 mL) and water (1.7 mL) were added potassium phosphate (3.70 g, 17.45 mmol) and cataCXium A Pd G3 (0.85 g, 1.16 mmol). The reaction mixture was stirred at 70 C for 2 h. The reaction mixture was purified by column chromatography on silica gel, eluting with 0-50% 3:1 Et0AciEt0H
blend in heptane with 2% triethylamine additive to yield 4-(benzyloxy)-7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol, 65 % yield). m/z (ESI):
645.0 (M+H)+.
Step 4: 7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-ol. 4-(Benzyloxy)-7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidine (2.42 g, 3.75 mmol) was dissolved in ethyl acetate (75 mL).
Palladium on activated carbon (0.80 g, 0.75 mmol) was added and the mixture stirred at rt under an atmosphere of H2 overnight. The mixture was filtered over celite and the filtercake washed with DCM:Me0H (2:1) until the filtrate ran clear. Volatiles were removed in vacuo to yield 7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-ol as a brown foam which was used without further purification. m/z (ESI): 555.0 (M+H)+.
7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate D)
- 133 -CI HO ' N 1\1 fli3u0K N 1\1 'Pr2NEt N 1\1 CI N CI CI CI N 0 ' THF MeCN
Step 1 Step 2 cataCXium A Pd G3 N 1\1 N 1\1 N 0 ' HCI
N 0 ' N
dioxane/water MeCN

Step 3 Step 4 Intermediate D
Step 1: 4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a stirring mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-dlpyrimidine (2.50 g, 9.90 mmol) in THF (3.5 mL) at -40 C was added slowly potassium tert-butoxide (1.0 Mm THF, 14.9 mL, 5 14.85 mmol) over a period of 0.5 h. Additional potassium tert-butoxide(1.0 Mm THF, 2.5 mL) was added after 1 h. The resulting mixture was stirred at -40 C for 10 min before being poured onto ice and saturated aqueous ammonium hydroxide followed by extraction with Et0Ac. The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, 10 eluting with a gradient of 0-20% Et0Ac in heptane to give 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-dlpyrimidine (1.12 g, 3.86 mmol, 39 % yield). m/z (ESI):
234.0 (M-13u+H)+.
Step 2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)pyrido[4,3-d]pyrimidine. A mixture of 4-(tert-butoxy)-2,7-15 dichloro-8-fluoropyrido[4,3-dlpyrimidine (0.58 g, 2.00 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.45 g, 2.80 mmol) and 1,1'-dimethyltriethylamine (1.03 g, 1.4 mL, 8.00 mmol) in MeCN (6.0 mL) in a 10-mL microwave reaction vessel was
- 134 -subjected to microwave irradiation (16 h at 75 C). Volatiles were removed under reduced pressure and the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% Me0H in DCM) in DCM to give 4-(tert-butoxy)-7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidine (0.66 g, 1.60 mmol, 80 % yield) as off-white solid. m/z (ESI):
413.2 (M+H)+.
Step 3: 4-(tert-Butoxy)-7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. In a 5-mL microwave reaction vessel were placed 4-(tert-butoxy)-7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidine (0.66 g, 1.60 mmol), 2-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.92 g, 2.56 mmol), cataCXium A Pd G3 (0.23 g, 0.32 mmol), and potassium phosphate tribasic (0.85 g, 4.00 mmol) followed by 1,4-dioxane (10 mL) and water (1.8 mL). The resulting mixture was purged with nitrogen for 10 min before being sealed and irradiated under microwave at 85 C for 3 h. Volatiles were removed under reduced pressure, and the crude residue was purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% Me0H in DCM) in DCM to give 4-(tert-butoxy)-7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidine (0.84 g, 1.38 mmol, 86 % yield) as colorless film. m/z (ESI): 611.2 (M+H)+.
Step 4: 7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yOmethoxy)pyrido14,3-d]pyrimidin-4-ol.
To a stirred solution of 4-(tert-butoxy)-7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidine (0.84 g, 1.38 mmol) in MeCN (2.0 mL) was added 4.0 M solution of HC1 in dioxane (12 mL, 48.1 mmol) at rt. The resulting mixture was stirred at rt for 0.5 h. Volatiles were removed under reduced pressure. The crude residue was dissolved in Me0H/DCM, cooled in an ice bath, and neutralized with ammonium hydroxide before loading onto a silica gel precolumn and purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% Me0H in DCM) in DCM to give 7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-
- 135 -d]pyrimidin-4-ol (0.39 g, 0.76 mmol, 56 % yield) as off-white solid. m/z (ESI): 511.0 (M+H)+.
7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-y1)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (Intermediate El) HO
CI
N NaSMe NN iPr2NEt N

CI NLCI MeCN

Step 1 Step 2 13,0 cataCXium A Pd G3 IN N

THF/water Step 3 Intermediate El Step 1: 2,7-Dichloro-8-fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine. To a stirring solution of 2,4,7-trichloro-8-fluoropyrido[4,3-dlpyrimidine (3.50 g, 13.86 mmol) in tetrahydrofuran (40 mL) at 0 C was added sodium methanethiolate (0.97 g, 13.9 mmol) in water (6 mL). The reaction was stirred at 0 C for 0.5 h and a precipitate was formed. The precipitate was collected by filtration to afford 2,7-dichloro-8-fluoro-4-(methylthio)pyrido[4,3-dlpyrimidine (2.10 g, 7.95 mmol, 57 % yield) as white solid, which was used directly in the subsequent step. m/z (ESI): 264.0 (M+H)+.
Step 2: 7-Chloro-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(51/)-y1)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine. A mixture of 2,7-dichloro-8-fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine (2.10 g, 7.95 mmol), ((2R,7aS)-2-
- 136 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.90 g, 11.93 mmol), and Hunig's base (4.11 g, 5.6 mL, 31.8 mmol) in acetonitrile (25 mL) was stirred at 70 C for 1.5 h. The reaction mixture was cooled to rt. The precipitate was collected by filtration and washed with heptane to afford a portion of the desired product. The filtrate was concentrated and purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20%
Me0H in DCM) in DCM to afford another portion of the desired product. Two portions were combined to give 7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-alpyrimidine (2.34 g, 6.05 mmol, 76 % yield) as orange solid. m/z (ESI): 387.0 (M+H)+.
Step 3: 7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)-4-(methylthio)pyrido[4,3-cipyrimidine. A mixture of 7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3 -al pyrimidine (2.34 g, 6.05 mmol), 2-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (3.27 g, 9.07 mmol), cataCXium A Pd G3 (0.88 g, 1.21 mmol), and potassium phosphate tribasic (3.85 g, 18.15 mmol) was suspended in degassed water (4 mL) and 1,4-dioxane (30 mL). The reaction was stirred at 85 C for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography twice, eluting with first a gradient of 0-50% (20% Me0H in DCM) in DCM, then 0-50% 3:1 Et0AciEt0H in heptane with 2% triethylamine additive to afford 7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(methylthio)pyrido[4,3 -al pyrimidine (1.50 g, 2.57 mmol, 42 % yield) as yellow solid. m/z (ESI): 585.0 (M+H)+.
7-(7,8-Difluoro-3-((triisopropylsilypoxy)naphthalen-l-y1)-8-fluoro-2-(02R,7aS)-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)-4-(methylthio)pyrido[4,3-4pyrimidine (Intermediate E2) FN N
N
OTIPS
- 137 -Intermediate E2 Synthesized in an analogous manner to Intermediate El. m/z (ESI): 687.0 (M+H)+.
(2S,4S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-fluoropyrrolidine (Intermediate Fl) =r=-=\....y0H NEt3, TBSCI F=r\.../OTBS
LNI LNI
DCM
Intermediate Fl ((2S,45)-4-Fluoropyrrolidin-2-yl)methanol hydrochloride (0.50 g, 3.20 mmol) was dissolved in DCM (16 mL) before triethylamine (0.49 g, 0.67 mL, 4.80 mmol) was added.
The solution cooled to 0 C. tert-Butylchlorodimethylsilane (0.53 g, 3.50 mmol) was then added in one portion. The mixture warmed to rt and then stirred overnight. The crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-35%
Me0H in DCM) to yield (2S,45)-2-4(tert-butyldimethylsilypoxy)methyl)-4-fluoropyrrolidine (0.38 g, 1.60 mmol, 50 % yield). m/z (ESI): 234.2 (M+H)+.
(R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)pyrrolidine (Intermediate F2) pTBS
mi, Intermediate F2 Synthesized in an analogous manner to Intermediate Fl from D-prolinol. m/z (ESI):
216.2 (M+H)+.
5,5-Dimethylpiperidine-3-carboxamide Hydrochloride (Intermediate Gl) 1. CU, MeCN
_____________________________ VP- HCI NH2 2. NH4OH MeCN 0 Step 1 Step 2 Intermediate G1 Step 1: tert-Butyl 5-carbamoy1-3,3-dimethylpiperidine-l-carboxylate. A
solution of 1,1'-carbonyldiimidazole (0.14 g, 0.87 mmol, Acros Organics) in acetonitrile (2.3 mL) was added dropwise to a stirring solution of 1-Rtert-butoxy)carbony11-5,5-dimethylpiperidine-3-
- 138 -carboxylic acid (0.21 g, 0.83 mmol, Enamine) in acetonitrile (3.2 mL). The reaction mixture was then allowed to stir at rt. After 1 h, ammonium hydroxide (4.20 g, 4.6 mL, 0.12 mol, Fisher Scientific) was added and the reaction was stirred at the same temperature overnight.
The organic solvent was removed under reduced pressure. The remaining solution was then diluted with Et0Ac (10 mL) and the organic layer was washed with 10% aq.
citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 5-carbamoy1-3,3-dimethylpiperidine-1-carboxylate (0.20g, 0.77 mmol, 92 % yield), which was used directly in the next step without further purification. m/z (ESI):
201.2 (M+H-Bu).
Step 2: 5,5-Dimethylpiperidine-3-carboxamide hydrochloride. A vial was charged with tert-butyl 5-carbamoy1-3,3-dimethylpiperidine-1-carboxylate (0.20g, 0.77 mmol) and acetonitrile (20 mL). HC1 (4 M in dioxane, 4.8 mL, 19 mmol, Sigma-Aldrich Corporation) was then added and the reaction was stirred at rt. After 1 h, the reaction was concentrated under reduced pressure to afford 5,5-dimethylpiperidine-3-carboxamide hydrochloride (0.14 g, 0.75 mmol, 97 % yield) as white solid. m/z (ESI): 157.2 (M+H)+.
re/-(1S,5S)-8-Azabicyclo13.2.11octane-2-carboxamide Hydrochloride (Intermediate G2) rj)LNH2 N HCI
Intermediate G2 Synthesized in an analogous manner to Intermediate GI using 8-Rtert-butoxy)carbony11-8-azabicyclo[3.2.11octane-2-carboxylic acid (Pharmablock, Inc.).
m/z (ESI): 155.2 (M+H)+.
re/-(1R,5R)-3-Azabicyclo13.2.11octane-1-carboxamide hydrochloride (Intermediate G3) n)(NH2 N HCI
- 139 -Intermediate G3 Synthesized in an analogous manner to Intermediate G1 using 3-Rtert-butoxy)carbony11-3-azabicyclo[3.2.11octane-1-carboxylic acid (Enamine). m/z (ESI): 155.2 (M+H)+.
3-Methylazepan-3-ol hydrochloride Isomer 1 (Intermediate H1) and Isomer 2 (Intermediate H2) 4Ik 0 *0 *0 HCI Cbz-CI Nr.0 Chiral Nr.0 Nr.0 DIPEA NN Separation THF
C
OH OH OH OH
Step 1 Step 2 Peak 1 Peak 2 H2, Pd/C
HCl/H20 H HCI H HCI
______________________ =
Et0H
OH OH
Step 3 Intermediate H1 Intermediate H2 Step 1: Benzyl 3-hydroxy-3-methylazepane-l-carboxylate. To a 100-mL round-bottomed flask was added 3-methylazepan-3-ol hydrochloride (0.25 g, 1.51 mmol, Asta-tech), benzyl chloroformate (0.28 g, 0.24 mL, 1.66 mmol, Oakwood Products, Inc.), DIPEA
(0.59 g, 0.8 mL, 4.53 mmol, Sigma-Aldrich Corporation) and THF (5.0 mL). The reaction was stirred at rt overnight. The solution was concentrated in vacuo. The crude material was purified by column chromatography on silica gel column, eluting with a gradient of 0 - 100%
Et0Ac in hexane to provide benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.33 g, 1.25 mmol, 83 % yield) as colorless oil. m/z (ESI): 264.2 (M+H)+.
Step 2: Chiral separation. Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.24 g) was purified via SFC using a Chiralpak IG, 21 x 250 mm 5 um, column with a mobile
- 140 -phase of 20% methanol with 0.2% triethylamine using a flowrate of 80 mL/min to generate 89 mg of peak 1 with an ee of >99% and 91 mg of peak 2 with an ee of >99%.
Step 3: 3-Methylazepan-3-ol hydrochloride. Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (89 mg, 0.34 mmol, Peak 1) was dissolved in ethanol (1.7 mL).
Palladium on activated carbon (74 mg, 0.07 mmol, Sigma-Aldrich Corporation) and aqueous HC1 solution (1 N, 0.2 mL, 0.42 mmol, Sigma-Aldrich Corporation) were added and the mixture stirred at rt under an atmosphere of H2 for 10 h. The catalyst was removed and the solution was concentrated to provide 3-methylazepan-3-ol hydrochloride (isomer 1, Intermediate H1, 60 mg, 0.36 mmol). Isomer 2, Intermediate H2 was obtained by the same method. m/z (ESI):
130.2 (M+H)+.
1,2,6,7-Tetrahydro-3H-azepin-3-one hydrochloride (Intermediate I) -+0 ric I __ HCI
HCI ric HN I

Intermediate I
To a 25-mL round-bottomed flask was added tert-butyl 3-oxo-2,3,6,7-tetrahydro-azepine-l-carboxylate (0.10 g, 0.47 mmol, AstaTech, Inc) and HC1 in 1,4-dioxane (4 M, 1.2 mL, 4.73 mmol, Sigma-Aldrich) in acetonitrile (2.4 mL). The reaction was stirred at rt overnight. The material was concentrated in vacuo to give a brown oil, which was used in the next step without further purification.
2,3,6,7-Tetrahydro-1H-azepin-3-ol hydrochloride (Intermediate J) o ric 1. NaBH4, THF HCIr-c I HN I
0 2. DCM/TFA
Intermediate J
To a 25-mL round-bottomed flask was added tert-butyl 3-oxo-2,3,6,7-tetrahydro-azepine-1-carboxylate (75 mg, 0.36 mmol, AstaTech, Inc) and sodium borohydride (40 mg, 1.07 mmol, Sigma-Aldrich Corporation) in THF (1.8 mL). A small amount of Me0H
was added and the reaction was stirred at rt for 1 h. The reaction mixture was diluted with
- 141 -saturated NH4 Cl (10 mL) and extracted with Et0Ac (2 x 10 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give a crude material, which was dissolved in 2 mL of DCM. At 0 C, 2 mL of TFA was addd. The reaction was stirred for 1 h. The mixture was concentrated in vacuo. To the residue was added 1 mL of 1 N HC1. The mixture was lyophilized to give 2,3,6,7-tetrahydro-1H-azepin-3-ol hydrochloride (60 mg, 0.40 mmol).
2,3,6,7-Tetrahydro-1H-azepine Hydrochloride (Intermediate K) HCI
TFA/MeCN CNH
Intermediate K
To a 25-mL round-bottomed flask was added tert-butyl 2,3,6,7-tetrahydro-1H-azepine-l-carboxylate (0.25 g, 1.27 mmol, AstaTech, Inc) in acetontrile (3.6 mL). TFA (0.74 g, 0.5 mL, 6.49 mmol, Sigma-Aldrich) was added at 0 C. The reaction was then stirred at r.t.
for 3 h thenconcentrated in vacuo. To the crude product was added HC1 solution (1 N, 2.5 mL, 2.53 mmol, Sigma-Aldrich). The material was lyophilized to give 2,3,6,7-tetrahydro-1H-azepine hydrochloride as off-white solid, which was used in the next step without any further purification.
8-Oxa-3-azabicyclo 13.2.11 octane-6- carb onitrile Hydrochloride (Intermediate L1) 6¨oH EiNH2 1. CD!, MeCN POCI3, imidazole ______________________________________________________ VP-2. NH4OH pyridine Step I Step 2 //
HCI
MeCN
HCI
0 0 Step 3 Intermediate LI
- 142 -Step 1: tert-Butyl 6-carbamoy1-3-azabicyclo13.2.21nonane-3-carboxylate. A
solution of 1,1'-carbonyldiimidazole (0.25 g, 1.56 mmol, Acros Organics) in acetonitrile (4.1 mL) was added dropwise to a stirring solution of 3-Rtert-butoxy)carbony11-3-azabicyclo[3.2.21nonane-6-carboxylic acid (0.40 g, 1.49 mmol, Enamine) in acetonitrile (5.8 mL). The reaction mixture was then allowed to stir at rt. After 1 h, ammonium hydroxide (7.50 g, 0.22 mol, Fisher Scientific) was added and the reaction was stirred at the same temperature. After stirring overnight, the organic solvent was removed under reduced pressure and then the reaction mixture was diluted with Et0Ac (10 mL) and the organic layer was washed with 10% aq. citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was then dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-carbamoy1-3-azabicyclo[3.2.21nonane-3-carboxylate (0.34 g, 1.26 mmol, 85 % yield). m/z (ESI): 213.2 (M+H-Bu). The product was then carried forward without further purification.
Step 2: tert-Butyl 6-cyano-3-azabicyclo13.2.21nonane-3-carboxylate. To a stirring solution of tert-butyl 6-carbamoy1-3-azabicyclo[3.2.21nonane-3-carboxylate (0.13 g, 0.47 mmol) in pyridine (1.2 mL) was added 1H-imidazole (63 mg, 0.93 mmol, Sigma Aldrich).
The resultant mixture was cooled to 0 C, and phosphorous oxychloride (0.29 g, 0.17 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added slowly dropwise and the mixture kept at the same temperature. After 1.2 h, the reaction was then quenched by the addition of saturated aqueous ammonium chloride (2 mL) and the aqueous layer extracted with Et0Ac (3 x 3 mL). The combined organic layers were then washed with 10% copper sulfate (2 x 10 mL), dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-cyano-3-azabicyclo[3.2.21nonane-3-carboxylate (94 mg, 0.38 mmol, 81 % yield).
m/z (ESI): 151.2 (M+H-Boc)+. The product was then carried forward without further purification.
Step 3: 8-Oxa-3-azabicyclo13.2.11octane-6-carbonitrile hydrochloride. tert-Butyl 6-cyano-3-azabicyclo[3.2.21nonane-3-carboxylate (94 mg, 0.38 mmol) was then dissolved in MeCN (3.5 mL) and HC1 in 1,4-dioxane (4 M, 0.47 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added. The reaction was then allowed to stir at rt for 15 min, and then the reaction was concentrated under reduced pressure to afford 3-azabicyclo[3.2.21nonane-6-
- 143 -carbonitrile hydrochloride (71 mg, 0.38 mmol, 82 % yield) as off-white solid.
The product was then carried forward without further purification. m/z (ESI): 151.2 (M+H)+.
3-Azabicyclo13.2.11octane-6-carbonitrile Hydrochloride (Intermediate L2) HCI
Intermediate L2 Synthesized in an analogous manner to Intermediate Li, using 34(tert-butoxy)carbony11-3-azabicyclo[3.2.11octane-6-carboxylic acid (CAS#: 2287288-75-7, Enamine). m/z (ESI): 137.1 (M+H)+.
(1S,5R)-2-Methyl-8-azabicyclo[3.2.1]octan-2-ol 2,2,2,-Trifluoroacetate (Intermediate M1) 1 MeMgBr, THF
Et0H

2. TFA, DCM HOACF3 Boc Intermediate M1 A round bottom flask was charged with tert-butyl (1S,5R)-2-oxo-8-azabicyclo[3.2.1loctane-8-carboxylate (0.50 g, 2.22 mmol, PharmaBlock) and THF
(12 mL).
The mixture was cooled to -78 C and MeMgBr (1.5 mL, 4.44 mmol) was added. The mixture was allowed to warm to rt. Upon completion, the reaction was quenched with brine and extracted with Et0Ac. The organic layer was dried and concentrated to give tert-butyl (1S,5R)-2-hydroxy-2-methyl-8-azabicyclo[3.2.1loctane-8-carboxylate as colorless oil, which was dissolved in DCM (3 mL) and TFA (0.5 mL, 6.67 mmol). The mixture was stirred at rt.
Upon completion, the reaction was concentrated in vacuo to give (1S,5R)-2-methy1-8-azabicyclo[3.2.1loctan-2-ol 2,2,2-trifluoroacetate (0.31 g, 2.22 mmol, 100 %
yield), which was used in the following step without further manipulation. m/z (ESI): 142.1 (M+H)+.
6-Methyl-2-azabicyclo12.2.11heptan-6-ol 2,2,2-Trifluoroacetate (Intermediate M2)
- 144 -d,OH

Intermediate M2 Synthesized in an analogous manner to Intermediate Ml, using tert-butyl 6-oxo-azabicyclo[2.2.11heptane-2-carboxylate (Enamine). m/z (ESI): 128.1 (M+H)+.
2-Azabicyclo12.2.11heptan-6-one hydrochloride (Intermediate N) ffo HCI
ff HCI
dioxane Boc Intermediate N
A round bottom flask was charged with tert-butyl 6-oxo-2-azabicyclo[2.2.11heptane-2-carboxylate (0.50 g, 2.37 mmol, Enamine) and 1,4-dioxane (11 mL). The mixture was cooled to -78 C and HC1 (4 M in dioxane, 1.78 mL, 7.10 mmol) was added. The mixture was allowed to stir at rt. Upon completion, the reaction was concentrated in vacuo to give 2-azabicyclo[2.2.11heptan-6-one hydrochloride (0.26 g, 2.37 mmol, 100 % yield) as white solid, which was used in the following step without further purification. m/z (ESI): 112.1 (M+H)+
2-(8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (Intermediate 0)
- 145 -CI CI CI CI Br AcONa H2SO4 NH201-1=HCI Ac20 Br2 Et0H/H20 NI, OH AcOH AcOH Br 0 NH2 HBr NH2 Step I Step 2 Step 3 CI Br CI Br DIPEA CI Br NaNO2 NaBH4 F MOMCI F
AcOH THF/Et0H DCM
propionic acid OH OMOM
Step 4 Step 5 Step 6 Pd(dppf)Cl2 KOAc, B2pIn2 CI 0õ0 B
DMF
Step 7 OMOM
Intermediate 0 Step 1: (E)-5-Chloro-6-fluoro-3,4-dihydronaphthalen-1(21/)-one oxime. To a solution of 5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (0.40 kg, 2.01 mol) in Et0H
(2.4 L) and H20 (0.8 L) was added Na0Ac (0.25 kg, 3.02 mol) and NH2OH=HC1 (0.21 kg, 3.02 mol). The reaction was stirred at 25 C for 12 h. Four reactions were carried out in parallel, and were combined for work up. The mixture was poured into ice, and then extracted with Et0Ac (3 L x 3). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give (E)-5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (1.60 kg, 83% yield, 88.9% purity) as yellow solid.
NMR: (400 MHz, CDC13) 6 7.81-7.78 (m, 1 H), 7.01 (t, J= 8.4 Hz, 1 H), 2.89-2.86 (m, 2 H), 2.82-2.79 (m, 2 H), 1.94-1.87 (m, 1 H).
Step 2: 5-Chloro-6-fluoronaphthalen-1-amine. To a solution of (E)-5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (0.26 kg, 1.22 mol) in AcOH (1.6 L) was added H2SO4 (0.36 kg, 3.65 mol, 0.2 L) and Ac20 (0.25 kg, 2.43 mol, 0.2 mL).
The mixture was stirred at 90 C for 2 h. Six reactions were carried out in parallel, and were combined for work up. Then the mixture was acidified with aqueous NaOH (15 L) till pH = 13 and
- 146 -extracted with Et0Ac (5 L x 2). The combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reversed phase HPLC (0.1% HC1 condition) to give 5-chloro-6-fluoronaphthalen-1-amine (0.35 kg, 24% yield, 99.5% purity) as red solid. 1HNMR: (400 MHz, CDC13) 6 7.69-7.66 (m, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.37-7.33 (m, 1 H), 7.21-7.17 (m, 1 H), 6.72 (d, J=
7.6 Hz, 1 H), 4.11 (s, 2 H).
Step 3: 2,4-Dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide. A
solution of 5-chloro-6-fluoronaphthalen-1-amine (93 g, 0.48 mol) in AcOH (0.65 L) was cooled to 0 C, then Br2 (0.30 kg, 1.90 mol, 98 mL) was added. The mixture was stirred at 25 C for 12 h. Three reactions were carried out in parallel, and were combined for work up. The mixture was filtered, the filter cake was washed with MTBE/MeCN = 3/1 (800 mL) to give 2,4-dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide (0.27 kg, 54%
yield) as brown solid.
Step 4: 5-Bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole. A solution of 2,4-dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide (0.15 kg, 0.34 mol) in AcOH (0.90 L) and propionic acid (0.37 L) was cooled to 0 C, then NaNO2 (27 g, 0.39 mol) was added. The mixture was stirred at 25 C for 2 h. Two reactions were carried out in parallel, and were combined for work up. The reaction mixture was quenched by addition H20 (2.0 L) at 20 C, and then filtered, the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE
(500 mL x 2) at 25 C for 30 min to give 5-bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,31oxadiazole (0.16 kg, 65% yield, 84% purity) as brown solid. 1HNMR: (400 MHz DMSO-d6) 6 7.76 -7.72 (m, 2 H), 7.34 (s, 1 H).
Step 5: 4-Bromo-5-chloro-6-fluoronaphthalen-2-ol. A solution of 5-bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,31oxadiazole (80 g, 0.27 mol) in Et0H (0.40 L) and THF
(0.16 L) was cooled to 0 C, then NaBH4 (20 g, 0.53 mol) was added. The mixture was stirred at 0 C for 1.5 h. Two reactions were carried out in parallel, and were combined for work up.
The reaction mixture was quenched by addition NH4C1 (1.0 L) at 0 C and then extracted with Et0Ac (0.5 mL x 2). The combined organic layers were washed with brine (0.5 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel, eluting with a graident
- 147 -of 1:0 ¨ 0:1 petroleum ether/Et0Ac to give 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (61 g, 42% yield) as brown solid. 1H NMR: (400 MHz DMSO-d6) 6 10.34 (s, 1 H), 7.88-7.84 (m, 1 H), 7.61 (s, 1 H), 7.57 (t, J= 9.2 Hz, 1 H), 7.31 (s, 1 H).
Step 6: 8-Bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene. A solution of 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (55 g, 0.20 mol) and DIPEA (77 g, 0.10 L, 0.60 mol) in DCM (0.33 L) was cooled to 0 C, then MOMC1 (32 g, 30 mL, 0.40 mol) was added to the mixture dropwise. The solution was warmed to 25 C and stirred for 12 h. The reaction mixture was quenched by addition saturated NaHCO3 (aq. 100 mL) at 25 C, and then diluted with DCM (500 mL) and washed with H20 (200 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel, eluting with a gradient of 20:1 ¨ 1:1 petroleum ether/Et0Ac to give 8-bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene (50 g, 73% yield, 93%
purity) as brown solid.
Step 7: 2-(8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane. A mixture of B2pin2 (62 g, 0.24 mol), 8-bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene (26 g, 81 mmol), Pd(dppf)C12 (6.0 g, 8.14 mmol), KOAc (20 g, 0.20 mol) in DMF (0.15 L) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 C for 8 h under N2 atmosphere.
Two reactions were carried out in parallel, and were combined for work-up. The reaction mixture was diluted with Et0Ac (500 mL) and washed with brine (500 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 100:1 ¨ 1:1 petroleum ether/Et0Ac. The crude product was re-purified by reversed phase HPLC
(neutral) to give 2-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (50.0 g) as white solid (38 g, 76% yield, 99% purity). NMR:
(400 MHz CDC13) 6 7.57 - 7.54 (m, 1 H), 7.32 (s, 2 H), 7.28-7.22 (m, 1 H), 5.20 (s, 2 H), 3.42 (s, 3 H), 1.37(s, 12H).
(3R)-1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-dipyrimidin-4-y1)-3-methylpiperidin-3-ol (Intermediate P)
- 148 Ds.1"OH 0¨.0H JOH CI
HCI NaSMe in H20 0". OH
I\V N KF, DMSO THF
I
N
N
CI N Ci DIPEA, CH3CN N
I
CI N CI F N CI N CI
step 1 F step 2 F step 3 Boin 0-.0H 0-.0H
OMOM NN m-CPBA NN
I I
CataCkum A Pd G2 Cs2CO3, Toluene, H20 step 4 OMOM step 5 OMOM
Intermediate P
Step 1. (R)-1-(2,7-Dichloro-8-fluoropyrido14,3-clipyrimidin-4-y1)-3-methylpiperidin-3-ol. To a mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-dlpyrimidine (25 g, 99 mmol, WuXi) in acetonitrile (500 mL) was added DIPEA (86 mL, 495 mmol) and (R)-3-methylpiperidin-3-ol hydrochloride (15 g, 99 mmol). The mixture was stirred at 0 C for 0.5 h under N2. The reaction mixture was diluted with water (1 L) and extracted with Et0Ac (0.9 L x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 50/1 to 0/1) to give (R)-1-(2,7-dichloro-8-fluoropyrido[4,3 -al pyrimidin-4-y1)-3- methylpiperidin-3-ol (28 g, 85 mmol, 85%
yield) as yellow solid.
Step 2: (R)-1-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yI)-3-methylpiperidin-3-ol. To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (20 g, 60.4 mmol) in dimethyl sulfoxide (300 mL) was added potassium fluoride (35 g, 604 mmol) . The mixture was stirred at 80 C for 12 h. The reaction mixture was partitioned between Et0Ac (2000 mL) and water (500 mL). The mixture was extracted with Et0Ac (500 mL x 3). The organic phase was separated, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was diluted with the mixture solution (Petroleum ether:
Et0Ac =20:1, 150 mL). The suspension was stirred at 20 C for 1 h. The mixture was then filtered through a fitted funnel. The filter cake was washed with MTBE (50 mL x 2) and concentrated under reduced pressure to give (R)-1-(7-chloro-2,8-difluoropyrido[4,3 -al pyrimidin-4-y1)-3-
- 149 -methylpiperidin-3-ol (15 g, 47.8 mmol, 79% yield) as yellow solid. m/z (ESI):
315.1, 317.1 (M+H)+.
Step 3: (R)-1-(7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol. To the mixture of (R)-1-(7-chloro-2,8-difluoropyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-ol (15 g, 47.7 mmol) in tetrahydrofuran (200 mL) was added sodium thiomethoxide (17 g, 47.7 mmol, 20% in H20) dropwise at 0 C. The mixture was stirred at 20 C for 2 h, diluted with H20 (100 mL) and Et0Ac (200 mL) and extracted with Et0Ac (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was triturated with a mixed solvent (Petroleum ether: Et0Ac=20:1, 500 mL) at 20 C
for 1 h. The suspension was filtered through a fitted funnel and the filter cake was washed with Petroleum ether:Et0Ac=20:1, 15 mL x 2. The filtrate was concentrated under reduced pressure to give (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol (15 g, 43 mmol, 90 % yield) as yellow solid.
Step 4: (R)-1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol. A
mixture of (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol (9.0 g, 26.3 mmol), 2-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11 g, 31.5 mmol, WuXi), cesium carbonate (17 g, 52.5 mmol) in 1,4-dioxane (170 mL) and water (15 mL) was degassed and purged with N2 for 3 times. CataCXium A Pd G2 (1.8 g, 2.63 mmol) was then added to the mixture and the reaction was stirred at 100 C for 8 h under N2. The reaction mixture was diluted with Et0Ac (200 mL) and water (200 mL), the layers were separated and the aqueous was extracted with Et0Ac (400 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography with (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (7.7 g, 14.3 mmol, 54%
yield) as white solid. m/z (ESI): 541.3, 542.3 (M+H)+.
Step 5: (3R)-1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-dipyrimidin-4-y1)-3-methylpiperidin-3-ol.
To the
- 150 -mixture of (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (7.0 g, 13.0 mmol) in dichloromethane (100 mL) was added m-CPBA (2.6 g, 13.0 mmol, 85% purity) in portions at 0 C. Then the mixture was stirred at 0 C for 1 h. The crude was purified by column chromatography directly (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give (3R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(methylsulfinyl)pyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-ol (5.0 g, 8.99 mmol, 69 %
yield) as yellow solid. m/z (ESI): 557.1 (M+H)+.
.. (R)-3-(Methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol (Intermediate Q1 and Q2) rf o OH pH
CD3Mg1 H2, Pd/C pH
0-.CD3 ____________________________________________________ v-HCI ________________ 40 THE, -78 C
40 Et0H
Step 1 Step 2 Peak 1 Peak 2 Intermediate Q1 Intermediate Q2 Step 1. (R)-3-(Methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol. A

solution of 1-benzylpiperidin-3-one hydrochloride (3.0 g, 13.3 mmol, AA
Blocks) in water (20 mL) was neutralized with potassium carbonate and extracted with ethyl acetate (50 mL).
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was redissolved in tetrahydrofuran (66 mL) and cooled to -78 C.
To the reaction was added methyl-d3-magnesium iodide solution (14.6 mL, 14.6 mmol, Sigma-Aldrich Corporation) dropwise. The reaction was stirred at -78 C. After 30 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate; the organic layer was concentrated. The crude product was purified by RP-MPLC chromatography, eluting with 0-50% (ACN/0.1% TFA) in (water/0.1% TFA).

The product fractions were combined, frozen, and lyophilized; the residue was redissolved in ethyl acetate, washed with aqueous potassium carbonate, and concentrated to provide 1-benzy1-3-(methyl-d3)piperidin-3-ol (1.6 g, 7.44 mmol, 56 % yield) as colorless oil. The racemic mixture was purified via SFC using a Chiralpak AD (21 x 250 mm Sum) column with a mobile phase of 10% methanol with 2% diethylamine using a flowrate of 120 mL/min,
- 151 -to provide two products. The first-eluting product (242 mg, 1.16 mmol, 8.7 %
yield, ee: >99 %) was assiged the R stereochemistry. The second-eluting product (227 mg, 1.09 mmol, 8.2 % yield, ee: >90 %) was assigned the S stereochemistry.
Step 2. (R)-3-(Methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol. A
solution of either (R)-1-benzy1-3-(methyl-d3)piperidin-3-ol (0.24 g, 1.16 mmol) or (5)-1-benzy1-3-(methyl-d3)piperidin-3-ol (0.23 g, 1.09 mmol) in ethanol (6.0 mL) was stirred under hydrogen atmosphere (25 psi). After 2 hours, the reaction mixture was filtered through Celite and concentrated in vacuo to provide the title compounds as colorless oils.
The isolated product were used in the next reactions without further purification;
quantitative yield was assumed.
5-Ethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (Intermediate R) Br 0 LaCI Br OH 4LiCI EtSiH, TFA Br EtMgBr, THE LJJ
Step I Step 2 N4 p\-r 0õ0 Br ,04 Br 4,4-tert-buty1-2,2i-dipyridyl H202/Acetic Acid B
2-MeTHF THF/water (3:1) HO
Step 3 Step 4 Br cLo 2,2-dimethylpropionyl chloride o B2Pin2/DPPF
TEA Toluene 0 >1)L0 Step 5 Step 6 Intermediate R
Step 1. 8-Bromo-1-ethy1-1,2,3,4-tetrahydronaphthalen-1-ol. To a 50-mL round-bottomed flask was added 8-bromo-3,4-dihydronaphthalen-1(2H)-one (0.72 g, 3.20 mmol, Ambeed, Inc.) and lanthanum(III) chloride bis(lithium chloride) complex solution, 0.6 M in THF (5.3 mL, 3.2 mmol, Sigma-Aldrich Corporation) in THF (13 mL). At 0 C,
- 152 -ethylmagnesium bromide, 3.0 Mmn diethyl ether (1.3 mL, 3.84 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was then diluted with saturated NH4C1 solution (10 mL) and extracted with Et0Ac (2 x 10 mL). The organic extract was washed with saturated NaCl solution ( 20 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 50% Et0Ac in heptane, to provide 8-bromo-1-ethy1-1,2,3,4-tetrahydronaphthalen-1-ol (0.71 g, 2.78 mmol, 87 % yield) as yellow oil. m/z (ESI): 237.2 (M+H-H20)+.
Step 2. 8-Bromo-1-ethy1-1,2,3,4-tetrahydronaphthalene. To a 25-mL round-bottomed flask was added 8-bromo-1-ethy1-1,2,3,4-tetrahydronaphthalen-1-ol (0.48 g, 1.88 mmol) in DCM (7.5 mL). After cooling to -30 C, triethylsilane (1.09 g, 9.41 mmol,) was added, followed by dropwise addition of TFA (0.64 g, 0.44 mL, 5.6 mmol). The reaction mixture was stirred for 3 h while slowly warming to rt. The reaction mixture was diluted with water (15 mL) and extracted with Et0Ac ( 2 x 15 mL). The organic extract was washed with saturated NaCl solution (15 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 20%
Et0Ac in heptane, to provide 8-bromo-1-ethy1-1,2,3,4-tetrahydronaphthalene (0.39 g, 1.63 mmol, 87 % yield) as colorless oil. m/z (ESI): 237.2 (M+H)+. 1HNMR (400 MHz, DMSO-d6) 6 ppm 7.35 - 7.48 (m, 1 H), 7.29 - 7.58 (m, 2 H), 2.64 - 2.89 (m, 3 H), 1.84 -2.04 (m, 1 H), 1.52- 1.85 (m, 4 H), 1.30- 1.45 (m, 1 H), 0.95- 1.05 (m, 3 H).
Step 3. 2-(4-Bromo-5-ethy1-5,6,7,8-tetrahydronaphthalen-2-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane. A 20-mL vial was charged with 8-bromo-1-ethy1-1,2,3,4-tetrahydronaphthalene (0.21 g, 0.88 mmol), 4,4,5,5-tetramethy1-1,3,2-dioxaborolane (0.28 g, 319 uL, 2.2 mmol, Sigma-Aldrich Corporation), 4,4'-di-tert-butyl-2,2'-dipyridyl (28 mg, 0.11 mmol), and di-u-methoxobis(1,5-cyclootadiene)diiridium(I) (58 mg, 0.088 mmol, Sigma-Aldrich Corporation). The reaction was purged with nitrogen for 5 min and then stirred at 65 C for 3 h. The reaction mixture was concentrated and the crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 70% Et0Ac in hexane, to provide 2-(4-bromo-5-ethy1-5,6,7,8-
- 153 -tetrahydronaphthalen-2-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (0.20 g, 0.55 mmol, 62 %
yield) as colorless oil.
Step 4. 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol. To a 50-mL round-bottomed flask was added 2-(4-bromo-5-ethy1-5,6,7,8-tetrahydronaphthalen-2-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (0.20 g, 0.55 mmol) in tetrahydrofuran (1.6 mL) and water (0.6 mL). After cooling to 0 C, hydrogen peroxide (0.56 g, 0.5 mL, 4.93 mmol) was added slowly, followed by addition of acetic acid (1.65 g, 1.6 mL, 27.4 mmol) dropwise. The reaction mixture was stirred for 3 h, and then diluted with Saturated Na2S203 solution (15 mL) and extracted with Et0Ac (2 x 15 mL). The combined organic layers were dried .. (Na2SO4) and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 -50% Et0Ac in hexane, to provide 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol as oil (0.120 g, 0.47 mmo1,86 % yield). m/z (ESI): 255.0 (M+H)+.
Step 5. 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-y1 pivalate. To a 50-mL
round-bottomed flask was added 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.12 g, 0.47 mmol) and triethylamine (0.16 mL, 0.94 mmol) in tetrahydrofuran (2.4 mL).
After cooling to 0 C, 2,2-dimethylpropionyl chloride (87 pL, 0.71 mmol) was added slowly. The reaction mixture was stirred for 1 h, and the crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 25%
Et0Ac in hexane, to provide 4-bromo-5-ethy1-5,6,7,8-tetrahydronaphthalen-2-ylpivalate (0.12 g, 0.35 mmo1,75 % yield) as oil.
Step 6. 5-Ethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6,7,8-tetrahydronaphthalen-2-y1 pivalate. A 20-mL vial was charged with 4-bromo-5-ethy1-5,6,7,8-tetrahydronaphthalen-2-ylpivalate (0.12 g, 0.35 mmol), bis(pinacalato)diboron (54 mg, 0.21 mmol), potassium acetate (0.10 g, 1.06 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (26 mg, 0.035 mmol) in toluene (2.4 mL). The reaction mixture was purged with nitrogen for 5 min and then stirred at 90 C for 3 h. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 60% Et0Ac in hexane, to provide 5-ethy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6,7,8-tetrahydronaphthalen-2-y1 pivalate as oil. m/z (ESI): 387.1 (M+H)+.
- 154 -5-Ally1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (Intermediate S) µ13' Piv0 Intermediate S
The intermediate was synthesized in a similar way to Intermediate R using 8-bromo-3,4-dihydro-2h-naphthalen-1-one (CAS#: 651735-60-3, Aurum Pharmatech LLC) and conducted Steps 3, 4, 5 before Step 1 (using allylzinc bromide, 0.5 M in THF) and Step 2, to generate 5-ally1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6,7,8-tetrahydronaphthalen-2-ylpivalate as oil. m/z (ESI): 399.2 (M+H)+.
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (Example 1)
- 155 -Oup CyS'NH2 0 0 Hee% N
HCI Cr 'NH2 CI
'Pr2NEt Pr2NEt N N N N
CH2Cl2 MeCN
*L, CI N CI CI N CI
Step I Step 2 =13 *00 0 0 0 0¨
CfS_NH2 Oe 'NH2 cataCXium A Pd G3 F N
NI \ N

Step 3 0 0 O= 'NH2 HCI in 1,4-Dioxane NI \ N
MeCN

OH
Step 4 Example I
Step 1: (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. To a 40-mL vial was added 2,4,7-trichloro-8-fluoropyrido14,3-d]pyrimidine (0.10 g, 0.40 mmol, WuXi) and DCM (4.0 mL). The mixture was cooled to -40 C, and then DIPEA (0.21 g, 0.28 mL, 1.58 mmol, Sigma-Aldrich) and (3R)-piperidine-3-sulfonamide hydrochloride (87 mg, 0.44 mmol, Enamine) was added. The reaction was then stirred at this temperature for 2 h. The reaction was then diluted with water (10 mL) and DCM
(10 mL).
The mixture was transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). Then the organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude orange oil. The crude residue was purified by column chromatography using a gradient
- 156 -of 0-50% 3:1 Et0AciEt0H (contatinng 2% triethylamine) in heptane to provide (R)-1-(2,7-dichloro-8-fluoropyrido[4,3 - cil pyrimidin-4-yl)piperidine-3-sulfonamide (95 mg, 0.25 mmol, 63 % yield) as white solid. m/z (ESI): 379.8 (M+H)+.
Step 2: (R)-1-(7-Chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yflmethoxy)pyrido14,3-d]pyrimidin-4-yflpiperidine-3-sulfonamide. To a 20-mL
vial was added 42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (52 mg, 0.32 mmol, LabNetwork), DIPEA (0.13 g, 0.17 mL, 1.00 mmol, Sigma-Aldrich), 4 A
molecular sieves (100 mg), (R)-1-(2,7-dichloro-8-fluoropyrido[4,3 - cil pyrimidin-4-yl)piperidine-3-sulfonamide (95 mg, 0.25 mmol) and acetonitrile (0.8 mL). The reaction was stirred at 75 C
overnight. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-75% 3:1 Et0AciEt0H (with 2% triethylamine) in heptane to provide (R)-1-(7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 - cil pyrimidin-4-yOpiperidine-3-sulfonamide (71 mg, 0.14 mmol, 57 %
yield) as yellow solid. m/z (ESI): 503.0 (M+H)+.
Step 3: (R)-1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yflmethoxy)pyrido[4,3-d]pyrimidin-4-yflpiperidine-3-sulfonamide. An 1 dram vial was charged with (R)-1-(7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-yOpiperidine-3-sulfonamide (50 mg, 0.10 mmol), 2-(8-.. ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg, 0.15 mmol, WuXi), potassium phosphate (63 mg, 0.30 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (90 4). The reaction was then sealed and heated to 70 C
for 12 h. The reaction was concentrated under reduced pressure to provide a black oil. The black oil was then purified by column chromatography on silica gel, eluting with a gradient of 0-100% 3:1 Et0AciEt0H (containing 2% triethylamine) in heptane to provide (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-yl)piperidine-3-sulfonamide (33 mg, .. 0.05 mmol, 48 % yield) as grey solid. m/z (ESI): 701.0 (M+H)+.
- 157 -Step 4: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. A vial was charged with (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-4-yl)piperidine-3-sulfonamide (33 mg, 0.05 mmol) and acetonitrile (1.5 mL). HC1 (4 M in 1,4-dioxane, 0.3 mL, 1.18 mmol, Sigma-Aldrich Corporation) was added and the reaction was stirred at room temperature for 15 min.
The reaction was then concentrated under reduced pressure and then purified via reverse phase HPLC to provide (R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]
pyrimidin-4-yl)piperidine-3-sulfonamide as bis(2,2,2-trifluoroacetate) and as yellow solid (20 mg, 0.02 mmol, 47 % yield). m/z (ESI): 657.2 (M+H)+. 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.20 (s, 1 H) 7.66 - 7.75 (m, 1 H) 7.34 (d, J=2.49 Hz, 1 H) 7.28 (s, 1 H) 7.07 (s, 1 H) 5.51 -5.72(m, 1 H) 5.01 (br s, 2 H) 4.67 - 4.82 (m, 1 H) 4.51 - 4.65 (m, 1 H) 3.75 -4.16 (m, 5 H) 3.43 -3.59 (m, 2 H) 2.55 -2.86 (m, 2 H) 2.33 -2.55 (m, 5 H) 2.01 -2.27 (m, 4 H) 1.78 - 1.91 (m, 1 H) 0.82 (br d, J=10.16 Hz, 3 H).
Table 2: Examples 2 to 42 and 170 to 175. Prepared in an analogous manner to Example 1.
Ex. Salt Method Structure Name Reagent Form Change 2 4-(4-(Azepan-1-y1)- Bis(2, Step 1:
8-fluoro-2- 2,2-hexamethylen N F (42R,7aS)-2- trifluo eimine fluorotetrahydro- roacet (CAS#: 111-' N 1H-pyrrolizin- ate) 49-9, Sigma-H 7a(5H)- Aldrich O
yl)methoxy)pyridop Corporation) ,3 -d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol
- 158 -Ex. Salt Method Structure Name Reagent Form Change 3 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
c?"--NH2 fluoro-3- trifluo pyrrolidine-3-hydroxynaphthalen- roacet carboxamide N N
1-y1)-8-fluoro-2- ate hydrochloride (((2R,7aS)-2- (CAS#:
N*Le6SN fluorotetrahydro- 644972-57-6, 1H-pyrrolizin- Enamine) OH 7a(511)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yl)pyrrolidine-3-carboxamide 4 (5)-1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo %pyrrolidine-2-N hydroxynaphthalen- roacet carboxylic Ntfk0 1-y1)-8-fluoro-2- ate acid amide (((2R,7aS)-2- (CAS#: 7531-OH fluorotetrahydro- 52-4, 1H-pyrrolizin- Enamine) 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yl)pyrrolidine-2-carboxamide 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
N NH2 fluoro-3- trifluo azetidine-2-N N F
hydroxynaphthalen- roacet carboxamide 1-y1)-8-fluoro-2- ate (CAS#:
(((2R,7aS)-2- 130973-78-3, fluorotetrahydro- Combi-Blocks OH
1H-pyrrolizin- Inc.) 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yl)azetidine-2-carboxamide
- 159 -Ex. Salt Method Structure Name Reagent # Form Change 041-12 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo isonipecotami hydroxynaphthalen- roacet de (CAS#:
F N
1-y1)-8-fluoro-2- ate 39546-32-2, N \, F (((2R,7aS)-2- Combi-Blocks i N*Le6"--5 fluorotetrahydro- Inc.) N
F 1H-pyrrolizin-OH 7a(511)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yl)piperidine-4-carboxamide 7 (:), 0 .,.. (S)-1-(7-(8-Ethy1-7- 2,2,2- Step 1: (35)-0' NH2 fluoro-3- trifluo piperidine-3 -F N hydroxynaphthalen- roacet sulfonamide F 1-y1)-8-fluoro-2- ate hydrochloride N \, : N
1 (((2R,7a5)-2- (CAS#:
F N fluorotetrahydro- 2322932-58-9, OH 1H-pyrrolizin- Enamine) 7a(511)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yl)piperidine-3-sulfonamide 8 Nu2 2-(1-(7-(8-Ethy1-7- 2,2,2- Step 1: 2-0 fluoro-3- trifluo (azetidin-3-hydroxynaphthalen- roacet yl)acetamide F N 1-y1)-8-fluoro-2- ate hydrochloride N F I \, N 65 (((2R,7aS)-2- (CAS#:
00' NIA,0,..-t,õ fluorotetrahydro- 1795493-56-9, N
F 1H-pyrrolizin- Enamine) OH 7a(511)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y0azetidin-3-ypacetamide
- 160 -Ex. Salt Method Structure Name Reagent Form Change 9 HO 3-(7-(8-Ethy1-7- hydro Step 1: 3-fluoro-3- chlori azabicyc1o113.2 hydroxynaphthalen- de .01heptan-6-ol * N
F 1-y1)-8-fluoro-2- (CAS#: ***- N
I (42R,7aS)-2- 1375065-64-7, 1111 F N fluorotetrahydro- Enamine) 1H-pyrrolizin-OH 7a(511)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.01hep tan-6-ol 00,on (R)-1-(7-(8-Ethy1-7- Bis(2, Step 1: (3R)-fluoro-3- 2,2- piperidin-3-ol ioN **==== N F
hydroxynaphthalen- trifluo (CAS#:
I N*Loõ,, 1-y1)-8-fluoro-2- roacet 62414-68-0, F (42R,7aS)-2-ate) Combi-Blocks fluorotetrahydro- Inc.) OH
1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido114 ,3 -al pyrimidin-4-yOpiperidin-3-ol (3S,4R)-1-(7-(8- 2,2,2- Step 1: cis-Ethy1-7-fluoro-3- trifluo 3,4-hydroxynaphthalen- roacet dihydroxypyrr hydrochloride 1-y1)-8-fluoro-2- ate re'o'"'= (((2R,7aS)-2-olidine fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 186393-21-5, 7a(5H)- Synthonix yl)methoxy)pyrido[4 Inc.) ,3 -al pyrimidin-4-yl)pyrrolidine-3,4-diol
- 161 -Ex. Salt Method Structure Name Reagent Form Change 12 00H (R)-1-(7-(7,8- 2,2,2- Step 1: (3R)-Difluoro-3- trifluo piperidin-3-ol hydroxynaphthalen- roacet (CA S#:
N
1-y1)-8-fluoro-2- ate 62414-68-0, Ne46---5N (((2R,7aS)-2- Combi-Blocks fluorotetrahydro- Inc.) OH 1H-pyrrolizin-7a(511)- Step 3: 2-(7,8-yl)methoxy)pyrido [4 difluoro-3-,3-d]pyrimidin-4- (methoxymeth yl)piperidin-3-ol oxy)naphthale n-1-y1)-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane (CAS#:
2621935-35-9, LabNetwork) 13 0.0H (R)-1-(7-(8-Ethyl-3- 2,2,2- Step 1: (3R)-hydroxynaphthalen- trifluo piperidin-3 -ol 1-y1)-8-fluoro-2- roacet (CA S#:
N
I õI (((2R,7aS)-2- ate 62414-68-0, fluorotetrahydro- Combi-Blocks 1H-pyrrolizin- Inc.) OH 7a(511)-yl)methoxy)pyrido [4 Step 3: 2-(8-,3-d]pyrimidin-4- ethy1-3-yOpiperidin-3-ol (methoxymeth oxy)naphthale n-1-y1)-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane (CAS#:
2621932-60-1, LabNetwork)
- 162 -Ex. Salt Method Structure Name Reagent Form Change 14 0, H (S)-1-(7-(8-Ethyl-7- 2,2,2-Step 1: (35)-fluoro-3- trifluo piperidin-3-ol F hydroxynaphthalen- roacet (CAS 24211-"
I )Leo4 1-y1)-8-fluoro-2- ate 55-0, Combi-0 F (((2R,7aS)-2- Blocks Inc.) fluorotetrahydro-OH
1H-pyrrolizin-7a(511)-yl)methoxy)pyrido114 ,3 -al pyrimidin-4-yOpiperidin-3-ol 15 won 5-Ethyl-6-fluoro-4- 2,2,2-Step 1: 3- Additional (8-fluoro-2- trifluo hydroxypiperi step F (42R,7aS)-2- roacet dine (CAS#:
between N N
fluorotetrahydro- ate 6859-99-0, Step 3 and 1H-pyrrolizin- Combi-Blocks Step 4.
7a(511)- Inc.) Details OH yl)methoxy)-4-(3- included methoxypiperidin-1- below.
yl)pyrido[4,3-al pyrimidin-7-yl)naphthalen-2-ol 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-fluoro-3- trifluo pyrrolidinol hydroxynaphthalen- roacet (CAS#:
1-y1)-8-fluoro-2- ate 40499-83-0, (((2R,7aS)-2- Synthonix fluorotetrahydro- Inc.) OH 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido114 ,3 -al pyrimidin-4-yl)pyrrolidin-3-ol
- 163 -Ex. Salt Method Structure Name Reagent Form Change 17 6Axon (1R,4S)-2-(7-(8- 2,2,2- Step 1: 2-F N Ethyl-7-fluoro-3- trifluo azabicyclo [2.2 vv N
F hydroxynaphthalen- roacet .2] octan-6-ol N
1-y1)-8-fluoro-2- ate (CAS#:
N (((2R,7a5)-2- 738551-49-0, fluorotetrahydro- Enamine) OH
1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114 ,3 -d] pyrimidin-4-y1)-2-azabicyclo 112 .2 .2] oct an-6-ol 3-(7-(7,8-Difluoro- 2,2,2- Step 1: 3-3- trifluo azabicyclo [3.2 hydroxynaphthalen- roacet .1loctan-6-ol F N N F 1-y1)-8-fluoro-2- ate hydrochloride (42R,7aS)-2- (CAS#:
N fluorotetrahydro- 2305252-97-3, 1H-pyrrolizin- Enamine) OH 7a(5H)-yl)methoxy)pyrido [4 Step 3: 2-(7,8-,3-d]pyrimidin-4- difluoro-3 -y1)-3 - (methoxymeth azabicyclo [3 .2 A] oct oxy)naphthale an-6-ol n-1-y1)-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane (CAS#:
2621935-35-9, LabNetwork)
- 164 -Ex. Salt Method Structure Name Reagent Form Change 19 5-Ethyl-6-fluoro-4- bis(2, Step 1: (S)-2-Step 2:
N OH (8-fluoro-2- 2,2-azetidinemeth NaH and N N (((2R,7aS)-2- trifluo anol THF
were ,6s fluorotetrahydro- roacea hydrochloride used.
1H-pyrrolizin- te) (CAS#:
OH 7a(511)- 791807-66-4, yl)methoxy)-4-((S)- Advanced 2- ChemBlocks (hydroxymethyl)azet Inc.) idin-l-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 20 4-(4-41S,5R)-3- bis(2, Step 1: Step 2:
Oxa-6- 2,2-(1S,5R)-3-oxa- NaH and F azabicyclo[3.2.01hep trifluo 6- THF
were N N
tan-6-y1)-8-fluoro-2- roacea azabicyclo[3.2 used.
(((2R,7a5)-2- te) .01heptane fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 2408936-87-6, 7a(5H)- Enamine) yl)methoxy)pyrido[4 ,3 -al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 21 r-- \c) re1-4-(44(1R,5R)-2- bis(2, Step 1: rel- Step 2:
Oxa-6- 2,2- (1R,5R)-2- NaH
and azabicyclo[3.2.01hep trifluo oxa-6- THF
were ri tan-6-y1)-8-fluoro-2- roacea azabicyclo[3.2 used.
Ne""' N (42R,7aS)-2- te) .01heptane fluorotetrahydro- hydrochloride OH
1H-pyrrolizin- (CAS#:
7a(5H)- 2137895-62-4, yl)methoxy)pyrido[4 Enamine) ,3 -al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol
- 165 -Ex. Salt Method Structure Name Reagent Form Change 22 ci HO\_Sõ.õ.. 4-(4-(3- bis(2, Step 1: 2-oxa-Step 2:
(Chloromethyl)-3- 2,2- 6- NaH
and (hydroxymethyl)pip trifluo azaspiro113.51n THF were NN F eridin-1-y1)-8- roacea onane used.
NeLe6--S
fluoro-2-(((2R,7aS)- te) hydrochloride 2-fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 1414885-19-0, 7a(511)- Enamine) yl)methoxy)pyrido[4 ,3 -al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3- Chiral fluoro-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .11octan-6-ol after Step F 1-y1)-8-fluoro-2- ate hydrochloride 3. Details N N
A (((2R,7aS)-2-No'65 (CAS#: included N fluorotetrahydro- 2305252-97-3, below.
1H-pyrrolizin- Enamine) OH 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11oct an-6-ol Isomer 1
- 166 -Ex. Salt Method Structure Name Reagent Form Change 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3- Chiral fluoro-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .11octan-6-ol after Step F 1-y1)-8-fluoro-2- ate hydrochloride 3. Details N N N
A (CAS#: included 63 (42R,7aS)-N fluorotetrahydro- 2305252-97-3, below.
1H-pyrrolizin- Enamine) OH 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11oct an-6-ol Isomer 2 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3- Chiral fluoro-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .11octan-6-ol after Step F 1-y1)-8-fluoro-2- ate hydrochloride 3. Details N""=41 A (42R,7aS)-2-(CAS#:
included N fluorotetrahydro- 2305252-97-3, below.
1H-pyrrolizin- Enamine) OH 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11oct an-6-ol Isomer 3
- 167 -Ex. Salt Method Structure Name Reagent Form Change 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3- Chiral fluoro-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .11octan-6-ol after Step F 1-y1)-8-fluoro-2- ate hydrochloride 3. Details /1 65 (42R,7aS)-2- (CAS#: included N fluorotetrahydro- 2305252-97-3, below.
1H-pyrrolizin- Enamine) OH 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.11oct an-6-ol Isomer 4 3-(7-(8-ethyny1-7- 2,2,2- Step 1: 3- Chiral fluoro-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .11octan-6-ol after Step V~N
F 1-y1)-8-fluoro-2- ate hydrochloride 1. Details (((2R,7aS)-2- (CAS#: included N fluorotetrahydro-1H- 2305252-97-3, below.
pyrrolizin-7a(5 H)- Enamine) OH Additional yl)methoxy)pyrido[4 ,3-dlpyrimidin-4- Step 3: 247-step after y1)-3- fluoro-3- Step 4.
azabicyclo[3.2.11oct (methoxymeth Procedure an-6-ol oxy)-8-[2-included [tris(1- below.
Isomer 1 methylethyl)si lyllethyny11-1-naphthalenyll-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS#:
2621932-37-2, LabNetwork)
- 168 -Ex. Salt Method Structure Name Reagent Form Change 3-(7-(8-ethyny1-7- 2,2,2- Step 1: 3- Chiral fluoro-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .1loctan-6-ol after Step F 1-y1)-8-fluoro-2- ate hydrochloride 1. Detail N N N
(42R,7aS)-2-N e"==
(2305252-97- included N fluorotetrahydro-1H- 3, Enamine) below.
pyrrolizin-7a(5H)-OH
yl)methoxy)pyridop Step 3: 247- Additional ,3-dlpyrimidin-4- fluoro-3- step y1)-3- (methoxymeth analogous azabicyclo[3.2.1loct oxy)-8-[2- to an-6-ol [tris(1-Example methylethyl)si 27 after Isomer 2 lyllethyny11-1- Step 4.
naphthalenyll-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS#:
2621932-37-2, LabNetwork) (1R,5R,6R)-3-(7-(8- 2,2,2- Step 1: 3- Chiral ethyl-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .1loctan-6-ol after Step N N
F 1-y1)-8-fluoro-2- ate hydrochloride 1. Detail N
I (42R,7aS)-2-NOS (CAS#:
included * F N fluorotetrahydro- 2305252-97-3, below.
1H-pyrrolizin- Enamine) OH 7a(511)-yl)methoxy)pyrido[4 Step 3: 2-(8-,3-d]pyrimidin-4- ethyl-3-y1)-3- (methoxymeth azabicyclo[3.2.1loct oxy)naphthale an-6-ol n-1-y1)-4,4,5,5-Isomer 1 tetramethyl-1,3,2-dioxaborolane (CAS#:
2621932-60-1, LabNetwork)
- 169 -Ex. Salt Method Structure Name Reagent Form Change (1R,5R,6R)-3-(7-(3- 2,2,2- Step 1: 3- Chiral chloro-2- trifluo azabicyc1o[3.2 separation cyclopropy1-5- roacet .1loctan-6-ol after Step V N N F hydroxypheny1)-8- ate hydrochloride 1. Detail CI * I N*Le',4 fluoro-2-(42R,7aS)- (CAS#:
included 2-fluorotetrahydro- 2305252-97-3, below.
OH 1H-pyrrolizin- Enamine) 7a(511)-yl)methoxy)pyrido[4 Step 3: 2-(3-,3-d]pyrimidin-4- chloro-2-y1)-3- cyclopropy1-5-azabicyclo[3.2.1loct (methoxymeth an-6-ol oxy)pheny1)-4,4,5,5-Isomer 1 tetramethyl-1,3,2-dioxaborolane (CAS#:
2621936-26-1, LabNetwork)
- 170 -Ex. Salt Method Structure Name Reagent Form Change (1R,5R,6R)-3-(7-(8- 2,2,2- Step 1: 3- Chiral ethyny1-3- trifluo azabicyclo[3.2 separation hydroxynaphthalen- roacet .1loctan-6-ol after Step F 1-y1)-8-fluoro-2- ate hydrochloride 1. Detail N ==== N
õ1 (42R,7aS)-2- (CAS#:
included 6-"S
N fluorotetrahydro- 2305252-97-3, below.
1H-pyrrolizin- Enamine) OH 7a(511)- Additional yl)methoxy)pyrido[4 Step 3: step ,3-d]pyrimidin-4-triisopropyl((6 analogous y1)-3- to azabicyclo[3.2.1]oct (methoxymeth Example an-6-ol oxy)-8- 27 after (4,4,5,5- Step 4.
Isomer 1 tetramethyl-1,3,2-dioxaborolan-yl)naphthalen-yl)ethynyl)sila ne (CAS#:
2621932-42-9, LabNetwork) 32 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 5,5-. fluoro-3- trifluo dimethylpiperi F (methoxymethoxy)n roacet din-3-ol N
NO>
aphthalen-l-y1)-8- ate hydrochloride N fluoro-2-(42R,7aS)- (CAS#:
2-fluorotetrahydro- 100868-99-3, OH 1H-pyrrolizin- Enamine) 7a(5H)-yl)methoxy)pyrido[4 ,3 -d] pyrimidin-4-y1)-5,5-dime thylpiperidin-3-ol
- 171 -Ex. Salt Method Structure Name Reagent Form Change 33 /0,0H (3R,65)-1-(7-(8- bis(2, Step 1:
ethyl-7-fluoro-3- 2,2- (3R,65)-6-F
hydroxynaphthalen- trifluo methylpiperidi N
I 1-y1)-8-fluoro-2- roacea n-3-ol (((2R,7aS)-2- te) hydrochloride fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 2227198-81-2, 7a(511)- Enamine) yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-6-methylpiperidin-3-ol 34 6,0H 8-(7-(8-Ethy1-7- bis(2, Step 1: endo-fluoro-3- 2,2- 8-hydroxynaphthalen- trifluo azabicyclo[3.2 N
I 1-y1)-8-fluoro-2- roacea .11octan-2-ol Ikr N (((2R,7aS)-2- te) (CAS#:
fluorotetrahydro- 92283-30-2, OH 1H-pyrrolizin- Pharmablock, 7a(5H)- Inc.) yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-y1)-8-azabicyclo[3.2.11oct an-2-ol 2,2,2-trifluoroacetate 35 (3R,45)-1-(7-(8- tris(2, Step 1:
c5o0H
Ethyl-7-fluoro-3- 2,2- (3R,45)-4-F hydroxynaphthalen- trifluo methyl-N ====N F 1-y1)-8-fluoro-2- roacea piperidin-3-ol N*Le165 (((2R,7aS)-2- te) hydrochloride N fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 1932604-01-7, 7a(5H)- J&W
yl)methoxy)pyrido[4 Pharmlab) ,3-dlpyrimidin-4-y1)-4-methylpiperidin-3-ol
- 172 -Ex. Salt Method Structure Name Reagent Form Change 36 0,0H (3R,6R)-1-(7-(8- tetraki Step 1:
Ethyl-7-fluoro-3- s(2,2, (3R,6R)-6-F
N
hydroxynaphthalen- 2- methylpiperidi 1-y1)-8-fluoro-2- trifluo II-3-o' (CA S# :
,*( N 0 " (((2R,7aS)-2- roacet 285995-17-7, fluorotetrahydro- ate) Enamine) OH 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114 ,3 -al pyrimidin-4-y1)-6-methylpiperidin-3 -ol 37 oR 5-Ethyl-6-fluoro-4- bi s (2, Step 1:
(8-fluoro-2- 2,2- hexahydro-2h-F (42R,7aS)-2- trifluo furo [2,3-N ===== F fluorotetrahydro- roace a clpyrrole I 1H-pyrrolizin- te) (CAS#:

7a(5H)- 1214875-23-6, yl)methoxy)-4- Advanced OH
(hexahydro-5H- ChemBlocks furo[2,3-clpyrro1-5- Inc.) yl)pyrido [4,3-d] pyrimidin-7-yl)naphthalen-2-ol 38 OH (R)-1-(7-(8-ethy1-7- bi s (2, Step 1: (3R)-Oto fluoro-3- 2,2- 3-F
hydroxynaphthalen- trifluo methylpiperidi N N N 1-y1)-8-fluoro-2- roace a n-3-ol ==== *'L
N 0 (((2R,7aS)-2- te) hydrochloride fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 2305080-34-4, 7a(5H)- Pharmablock) yl)methoxy)pyrido 114 ,3 - cil pyrimidin-4-y1)-3 -methylpiperidin-3 -ol
- 173 -Ex. Salt Method Structure Name Reagent Form Change 3-(Difluoromethyl)- 2,2,2- Step 1: 3- Chiral 1-(7-(8-ethy1-7- trifluo (difluorometh separation fluoro-3- roacet yl)piperidin-3- after Step hydroxynaphthalen- ate ol 1.
Details Ne".= 1-y1)-8-fluoro-2-hydrochloride included (42R,7aS)-2- (CAS#: below.
OH fluorotetrahydro- 1909325-03-6, 1H-pyrrolizin- Enamine) 7a(511)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yOpiperidin-3-ol Isomer 1 3-(Difluoromethyl)- 2,2,2- Step 1: 3- Chiral 1-(7-(8-ethy1-7- trifluo (difluorometh separation fluoro-3- roacet yl)piperidin-3- after Step hydroxynaphthalen- ate ol 1.
Details Ne".= 1-y1)-8-fluoro-2-hydrochloride included (42R,7aS)-2- (CAS#: below.
OH fluorotetrahydro- 1909325-03-6, 1H-pyrrolizin- Enamine) 7a(5H)-yl)methoxy)pyrido[4 ,3 -al pyrimidin-4-yOpiperidin-3-ol Isomer 2
- 174 -Ex. Salt Method Structure Name Reagent Form Change F 3-(Difluoromethyl)- 2,2,2- Step 1: 3- Chiral 1-(7-(8-ethyny1-7- trifluo (difluorometh separation fluoro-3- roacet yl)piperidin-3- after Step hydroxynaphthalen- ate ol 1.
Details 1-y1)-8-fluoro-2-hydrochloride included (42R,7aS)-2- (CAS#: below.
OH fluorotetrahydro- 1909325-03-6, 1H-pyrrolizin- Enamine) Additional 7a(511)- step yl)methoxy)pyrido[4 Step 3: 247- analogous ,3-d]pyrimidin-4- fluoro-3- to yl)piperidin-3-ol (methoxymeth Example oxy)-8-[2- 27 after Isomer 1 [tris(1- Step 4.
methylethyl)si lyllethyny11-1-naphthalenyll-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS#:
2621932-37-2, LabNetwork) ao) re/-5-Ethy1-6-fluoro- 2,2,2- Step 1: rac-F 4-(8-fluoro-2- trifluo (3aR,7aR)-F (42R,7aS)-2- roacet octahydrofuro N ==== N
I N*Lek, fluorotetrahydro- ate N 1H-pyrrolizin- b] pyridine 7a(5H)- (CAS#:
OH
yl)methoxy)-4- 1909293-80-6, ((3aR,7aR)- Enamine) hexahydrofuro[3,2-blpyridin-4(2H)-yl)pyrido[4,3-d] pyrimidin-7-yl)naphthalen-2-ol
- 175 -Ex. Salt Method Structure Name Reagent # Form Change 170 _oL-1 (R)-1-(7-(8-Ethy1-7- bis(2, Step 1:
fluoro-3- 2,2- 2,4,7-N F
hydroxynaphthalen- trifluo trichloropyrid F., N N 1-y1)-2-(((2R,7aS)-2- roacet o114,3-fluorotetrahydro- ate) dlpyrimidine 1H-pyrrolizin- (CAS#:
OH 7a(511)- 2384434-96-0, yl)methoxy)pyridop eNovation ,3-d]pyrimidin-4- Chemicals y1)-3- LLC) methylpiperidin-3-ol 171 F 1-(7-(8-Ethy1-7- 2,2,2-Step 1: 3- Chiral r1OH fluoro-3- trifluo (fluoromethyl) separation N hydroxynaphthalen- roacea piperidin-3-ol after Step F
F 1-y1)-8-fluoro-2- te hydrochloride 1. Details N r\J
1 (42R,7aS)-2- (CAS#:
included N '6--- fluorotetrahydro- 2306262-40-6, below.
F
1H-pyrrolizin- AChem OH 7a(5H)- Block) yl)methoxy)pyrido[4 ,3-d] pyrimidin-4-y1)-3-(fluorome thyl)piperi din-3-ol Isomer 1 172 F 1-(7-(8-Ethy1-7- 2,2,2-Step 1: 3- Chiral COH fluoro-3- trifluo (fluoromethyl) separation N hydroxynaphthalen- roacea piperidin-3-ol after Step F
F 1-y1)-8-fluoro-2- te hydrochloride 1. Details N
1 (42R,7aS)-2- (CAS#:
included fluorotetrahydro-1H- 2306262-40-6, below.
F
pyrrolizin-7a(5H)- AChem OH
yl)methoxy)pyrido[4 Block) ,3 -d] pyrimidin-4-y1)-3-(fluorome thyl)piperi din-3-ol Isomer 2
- 176 -Ex. Salt Method Structure Name Reagent Form Change 173 C. (3R)-1-(7-(8-ethyl- 2,2,2- Step 3: Chiral OH
3 -hydroxy-5,6,7,8- trifluo Intermediate R separation tetrahydronaphthale roacea after Step NotC-j.. F n-1-y1)-8-fluoro-2- te 3.
Details (((2R,7aS)-2-included HO fluorotetrahydro- below.
1H-pyrrolizin- Step 4: 5 7a(5H)- N NaOH
yl)methoxy)pyrido [4 in Me0H
,3-dlpyrimidin-4- was used.
y1)-3 -methylpiperidin-3 -ol Isomer 2 174 (3R)-1-(7-(8-ethyl- 2,2,2- Step 3:
Chiral 3 -hydroxy-5,6,7,8- trifluo Intermediate R separation N N
tetrahydronaphthale roacea after Step NotC-3.*F n-1-y1)-8-fluoro-2- te 3.
Details (42R,7aS)-2-included HO fluorotetrahydro- below.
1H-pyrrolizin- Step 4: 5 7a(5H)- N NaOH
yl)methoxy)pyrido [4 in Me0H
,3-d]pyrimidin-4- was used.
y1)-3 -methylpiperidin-3 -ol Isomer 1 175 CJOH (3R)-1-(7-(8-Allyl- 2,2,2- Step 2: Step 4: 5 3 -hydroxy-5,6,7,8- trifluo Intermediate S N NaOH
N
tetrahydronaphthale roacea in Me0H
n-1-y1)-8-fluoro-2- te was used.
(42R,7aS)-2-HO fluorotetrahydro-1H-pyrrolizin-7 a(5H)-yl)methoxy)pyrido 114 ,3 -dlpyrimidin-4-y1)-3 -methylpiperidin-3 -ol
- 177 -Table 3: SFC conditions for chiral separation.
Peaks to Compound SFC Conditions Ex. #
Round I Peak 1:
Column: ChiraIcel 0J, 30 x 150 mm 5um.
Example Mobile phase: 25% methanol 27 Ficnvrate: 200 mUmin Yield: 3.3 g sample was submitted to generate 1.19g of Peak 2:
peak HO 1 with an co of <80%, 1.08 a of peak 2 with an ee of Example >99%, and 1.01 g of peak 3-4, 24 Example Round 2 (peak 1) 28 Reprocessed using under the same conditions to generate Example LO 1 g of peak 1 with an to of >99%. 29 ...---CI N CI
Example Round 3 (peak 3-4) 30 Column: Chiralcel 01121 x 150 mm Sum Example Mobile phase: 35% methanol 31 Flowrate: 80 aiLlmin Yield: 0.46 a of peak 3 with an ee of >99% and 0.48 g of peak 4 with an ee of >99%.
HO l\JUflu1 Peak 1:
Column: (S,S) Whelk 04 column, 21 x 250 mm Example Mobile phase: 55% CO2 and 45% methanol w/ 0.2% 23 NN 1F diethylamine *Leõõ Flowrate: 80 inUmin Peak 2:
N
N Yield: 121 mg swnple was submitted to generate 50 mg of Example peak 1. and 2 and 23 mg of peak 3 and 4. 24 o o Round 2 (peak 1 and 2) Peak 3:
Column: Chiralpak 1E column, 21 x 150 min Example Mobile phase: 40% CO2 and 60% methanol w/ 0.2% 25 diethylamine Flowrate: 80 in', Peak 4:
Yield: 21.3 mg of peak 1 with ee> 99% and 22.7 Mg of Example peak 2 with ee> 98%. 26 Round 3 (peak 3 and 4) Column: Chiralpak IF column, 2.1 x 150 mm Mobile phase: 40% CO2. and 60% methanol Iv/ 0.2%
triethylamine Flowrate: 80 mumin Yield: 7.6 mg of peak 1 with ee> 75% and 9.4 mg of peak 2 with ee> 89%.
- 178 -OH Column: ChiralPak IG, 2 x 15 cm 5 tun Peak 1:
OLcHF, Mobile phase: 25% Me014 Example Flowrate: 80 iriLimin 39 N N Yield: 739 mg of sample was submitted to generate 360 Example mg, of peak 1 with an ee of 99% and 341 mg of peak 2 41 CI N CI
ith an 'e of 99%.
Peak 2:
Example F\ Column: Chi ralPak 1G, 2 x 25 ern 5 pm ZOH Mobile phase: 30% Me0flw/ 0.2% TEA
Flowrate: 80 mL/min.
Yield: 641 mg sample was submitted to generate 283 mg NN of peak 1 with an ee of 99% and 285 mg of peak 2 with an CI N CI ee of 96%.
nOH Column: (S,S) Whelk-01, 21 x 250 mm Sulu µ
Mobile phase of 35% ethanol with 0.2% diethylamine N N using a Flowrate: 100 mL/min Yield: 33 mg sample was submitted to generate 14.7 mg of peak 1 with an ee of >99% and 18 mg of peak 2 with an oo ee of >99%.
Additional Step for Example 15 HO
N N NaH, Mel N N
N0 N 0 "
THF
(0 (0 To a 20-mL vial was added 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-5 1-y1)-8-fluoro-2-(42S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido14,3-alpyrimidin-4-y1)piperidin-3-ol (0.10 g, 0.16 mmol, synthesized in an analogous manner to Example 1) and sodium hydride (19 mg, 0.47 mmol, TCI America) in tetrahydrofuran (1.6 mL) at 0 C. The reaction was stirred at 0 C for 20 min. Next, iodomethane (45 mg, 0.02 mL, 0.31 mmol, Sigma-Aldrich Corporation) was added and the reaction was warmed to rt 10 for 2 h. The reaction mixture was diluted with water and extracted with CH2C12. The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give
- 179 -the crude material as light-yellow solid. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% Et0Ac in heptane to provide 7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-y1)pyrido[4,3-dlpyrimidine as light-yellow solid. m/z (ESI): 652.3 (M+H)+.
Additional Step for Example 27 HO HO
TIPS e F CsF
N N N N
DMF
N 0 4 N 0 =
OH OH
To a solution of 3-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-azabicyclo[3.2.11octan-6-ol (0.15 g, 0.19 mmol) in N,N-dimethylformamide (1.9 mL) was added cesium fluoride (0.25 g, 1.61 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at rt for 2-d.
The reaction mixture was partitioned between Et0Ac and water. The aqueous layer was back extracted with Et0Ac and the combined organics was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to provide 34748-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -azabicyclo [3 .2. lloctan-6-ol as 2,2,2-trifluoroacetate and as off-white solid (70 mg, 0.10 mmol, 50% yield).
Table 4: Analytical Data of Examples 2 to 42 and 170 to 175.
- 180 -E MS
x.
m/z (ESI): 11-1 NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.23 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.09 (d, J=2.5 Hz, 1 H), 5.46 - 5.74 (m, 1 H), 4.64 - 4.74 2 592.2 (m, 2 H), 4.14 -4.27 (m, 4 H), 3.82 -4.10 (m, 3 H), 3.45 - 3.53 (m, 1 H), 2.58 -2.82 (m, 2 H), 2.33 -2.57 (m, 4 H), 2.13 -2.28 (m, 2 H), 2.04 - 2.13 (m, 4 H), 1.70 - 1.79 (m, 4 H), 0.83 (t, J=7.0 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.35 (s, 1 H) 7.65 -7.75 (m, 1 H) 7.34 (d, J=2.72 Hz, 1 H) 7.27 (s, 1 H) 7.08 (d, 607.0 J=2.09 Hz, 1 H) 5.47 - 5.67 (m, 1 H) 4.63 - 4.75 (m, 2 H) 3.80 -4.39 (m, 7 H) 3.43 - 3.54 (m, 1 H) 3.35 - 3.40 (m, 1 H) 2.54 -2.82 (m, 2 H) 2.29 -2.54 (m, 6 H) 2.12 -2.26 (m, 2 H) 0.77 - 0.85 (m, 3H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.23 - 9.50 (m, 1 H) 7.71 (dd, J=8.99, 5.85 Hz, 1 H) 7.34 (d, J=2.72 Hz, 1 H) 7.28 (s, 1 6069. H) 7.03 - 7.11 (m, 1 H) 5.50 - 5.71 (m, 1 H) 4.86 - 4.98 (m, 1 H) 4 4.65 (br d, J=2.09 Hz, 2 H) 4.22 - 4.45 (m, 2 H) 3.96 -4.15 (m, 1 H) 3.83 - 3.96 (m, 2 H) 3.44 - 3.54 (m, 1 H) 2.57 - 2.80 (m, 2 H) 2.44 -2.57 (m, 2 H) 2.38 (br d, J=4.60 Hz, 4 H) 2.12 - 2.29 (m, 4 H) 0.81 (t, J=7.42 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.00 - 9.10 (m, 1 H) 7.65 - 7.77 (m, 1 H) 7.34 (d, J=2.49 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 592.9 7.06 (br d, J=2.70 Hz, 1 H) 5.48 - 5.69 (m, 1 H) 4.89 - 5.26 (m, 3 H) 4.58 - 4.77 (m, 2 H) 3.82 - 4.14 (m, 3 H) 3.42 - 3.54 (m, 1H) 2.84 - 3.02 (m, 1 H) 2.37 (br d, J=2.70 Hz, 7H) 2.10 -2.25 (m, 2 H) 0.77 - 0.84 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.14 (s, 1 H) 7.66 -7.76 (m, 1 H) 7.33 - 7.39 (m, 1 H) 7.23 - 7.32 (m, 1 H) 7.08 (d, 6 621.2 J=2.70 Hz, 1 H) 5.47 - 5.70 (m, 1 H) 4.62 - 4.83 (m, 4 H) 3.84 -4.15 (m, 3 H) 3.54 - 3.68 (m, 2 H) 3.45 -3.54 (m, 1 H) 2.66 (br s, 3 H) 2.37 (br s, 4H) 2.14 -2.28 (m, 2H) 2.04 - 2.14 (m, 2H) 1.89 - 2.04 (m, 2 H) 0.77 - 0.87 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.20 (s, 1 H) 7.71 (dd, J=9.12, 5.80 Hz, 1 H) 7.34 (d, J=2.70 Hz, 1 H) 7.28 (s, 1 H) 7.03 - 7.11 (m, 1 H) 5.49 - 5.69 (m, 1 H) 4.94 - 5.06 (m, 1 H) 4.65 7 657.2 -4.81 (m, 2 H) 4.49 - 4.64 (m, 1 H) 3.76 - 4.14 (m, 5 H) 3.42 -3.58 (m, 2 H) 2.55 - 2.84 (m, 2 H) 2.34 - 2.52 (m, 5 H) 2.01 - 2.29 (m, 4 H) 1.76- 1.92(m, 1 H) 0.71 - 0.88 (m, 3 H).
- 181 -E MS
x.
m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.00 (s, 1 H) 7.70 (dd, J=8.99, 5.85 Hz, 1 H) 7.33 (d, J=2.72 Hz, 1 H) 7.27 (t, J=9.30 Hz, 1 H) 7.05 (d, J=2.51 Hz, 1 H) 5.47 - 5.69(m, 1 H) 4.97 -5.17 8 606.9 (m, 1 H) 4.70 (br dd, J=16.30, 4.39 Hz, 4 H) 4.15 -4.36 (m, 1 H) 3.80 - 4.13 (m, 3 H) 3.42 - 3.56 (m, 1 H) 3.35 (br s, 1 H) 2.76 (d, J=7.52 Hz, 4 H) 2.31 -2.52 (m, 4 H) 2.10 - 2.25 (m, 2 H) 0.81 (s, 3H).
IHNMR (METHANOL-4 400 MHz) 6 9.44 (br d, 1H, J=9.0 Hz), 7.74 (dd, 1H, J=5 .7 , 8.9 Hz), 7.39 (d, 1H, J=2.3 Hz), 7.31 (t, 1H, J=9.4 Hz), 7.15 (d, 1H, J=2.3 Hz), 5.5-5.7 (m, 1H), 4.83 (br d, 606.3 9 3H, J=8.2 Hz), 4.42 (td, 2H, J=7.3, 14.3 Hz), 3.7-3.8 (m, 1H), 3.7-4.0 (m, 3H), 3.6-3.7 (m, 2H), 3.5-3.6 (m, 2H), 3.4-3.5 (m, 1H), 2.6-2.7 (m, 2H), 2.3-2.5 (m, 5H), 2.2-2.3 (m, 2H), 1.6-1.8 (m, 1H), 0.87 (br t, 3H, J=7.3 Hz).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.25 (d, J=5.9 Hz, 1 H), 7.70 (dd, J=9.2, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (s, 1 H), 7.07 (t, J=3.1 Hz, 1 H), 5.50 - 5.69 (m, 1 H), 4.61 -4.71 (m, 594.3 2 H), 3.81 -4.28 (m, 8 H), 3.45 - 3.58 (m, 1 H), 2.71 -2.80 (m, 1 H), 2.53 - 2.63 (m, 1 H), 2.33 - 2.51 (m, 4 H), 2.04 - 2.30 (m, 4 H), 1.70 - 1.86 (m, 2 H), 0.74 - 0.88 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.34 (s, 1 H), 7.70 (dd, J=9.0, 5.6 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.23 - 7.31 (m, 1 H), 7.09 (d, J=2.5 Hz, 1 H), 5.44 - 5.78 (m, 1 H), 4.71 (br d, J=4.4 11 596.2 Hz, 2 H), 4.40 -4.46 (m, 2 H), 4.04 - 4.12 (m, 2 H), 3.83 - 3.97 (m, 3 H), 3.45 - 3.57 (m, 1 H), 2.71 -2.88 (m, 1 H), 2.30 - 2.62 (m, 6 H), 2.07 -2.24 (m, 2 H), 1.63 - 1.64 (m, 1 H), 0.82 (br t, J=7.2 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.22 - 9.28 (m, 1 H), 7.64 (ddd, J=9.3, 4.8, 1.6 Hz, 1 H), 7.34 - 7.46 (m, 2 H), 7.28 (br d, J=4.0 Hz, 1 H), 5.49 - 5.70 (m, 1 H), 4.71 (br d, J=15.9 Hz, 2 12 584.2 H), 4.25 (br d, J=12.8 Hz, 1 H), 3.82 - 4.20 (m, 8 H), 3.46 - 3.57 (m, 1 H), 2.69 - 2.84 (m, 1 H), 2.55 - 2.66 (m, 1 H), 2.32 - 2.47 (m, 3 H), 2.11 - 2.22 (m, 2 H), 1.72 - 1.86 (m, 2 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.21 -9.26 (m, 1 H), 7.61 - 7.70 (m, 1 H), 7.38 (m, J=8.2 Hz, 1 H), 7.32 (d, J=2.7 Hz, 1 H), 7.19 (d, J=6.9 Hz, 1 H), 7.04 (t, J=3.0 Hz, 1 H), 5.47 - 5.73 13 576.3 (m, 1 H), 4.71 (br dd, J=16.5, 4.2 Hz, 2 H), 3.83 -4.29 (m, 9 H), 3.56 (s, 1 H), 2.69 - 2.85 (m, 1 H), 2.66 (br s, 1 H), 2.24 - 2.50 (m, 5 H), 2.05 - 2.19 (m, 2 H), 1.72 - 1.88 (m, 2 H), 0.92 (td, J=7.4, 3.8 Hz, 3 H).
- 182 -E MS
x.
m/z (ESI): 11-1 NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.22 - 9.29 (m, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (t, J=2.7 Hz, 1 H), 5.51 - 5.68 (m, 1 H), 4.62 14 594.1 - 4.74 (m, 2H), 4.10 - 4.27 (m, 2H), 3.83 - 4.08 (m, 6H), 3.44 -3.55 (m, 1 H), 2.73 - 2.81 (m, 1 H), 2.55 - 2.63 (m, 1 H), 2.43 -2.52 (m, 2 H), 2.33 - 2.42 (m, 2 H), 2.04 - 2.30 (m, 4 H), 1.71 -1.89 (m, 2 H), 0.82 (t, J=7.4 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.24 (d, J=1.0 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=1.0 Hz, 1 H), 7.08 (dd, J=6.0, 2.6 Hz, 1 H), 5.59 (dt, J=1.0 Hz, 1 H), 4.62 -4.70 (m, 1 H), 4.26 -4.46 (m, 2 H), 4.03 -4.13 (m, 2 H), 15 608.4 3.87 - 3.98 (m, 2 H), 3.72 - 3.86 (m, 2 H), 3.62 -3.70 (m, 1H), 3.46 -3.54 (m, 1 H), 3.34 - 3.36 (m, 3 H), 2.68 -2.81 (m, 1 H), 2.63 - 2.66 (m, 1 H), 2.54 - 2.63 (m, 1 H), 2.31 - 2.53 (m, 4 H), 2.20 (br s, 2 H), 1.97 -2.04 (m, 2 H), 1.78 (br s, 1 H), 0.82 (t, J=7.4 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.36 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=1.0 16 580.3 Hz, 1 H), 7.07 (dd, J=1.0 Hz, 1 H), 5.57 (dt, J=1.0 Hz, 1 H), 4.60 -4.70 (m, 3 H), 3.83 -4.13 (m, 5 H), 3.44 - 3.55 (m, 2 H), 2.69 -2.81 (m, 1 H), 2.32 - 2.67 (m, 6 H), 2.09 - 2.32 (m, 4 H), 0.76 -0.89 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.25 - 9.44 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 17 620.4 H), 7.07 (t, J=2.4 Hz, 1 H), 5.39 - 5.75 (m, 1 H), 4.60 - 4.73 (m, 2 H), 4.22 -4.35 (m, 1 H), 3.91 (m, J=15.5 Hz, 5 H), 3.44 - 3.55 (m, 1 H), 2.11 -2.81 (m, 12 H), 1.93 -2.08 (m, 1 H), 1.73 - 1.92 (m, 2 H), 1.63 (br d, J=13.0 Hz, 1 H), 0.76 - 0.87 (m, 3 H).
1H NMR (METHANOL-d4, 400 MHz) 6 9.32 (s, 1H), 9.17 (s, 1H), 7.64 (ddd, 1H, J=1.4, 4.8, 9.3 Hz), 7.4-7.5 (m, 1H), 7.2-7.4 (m, 18 610.2 2H), 5.5-5.7 (m, 1H), 4.8-5.0 (m, 2H), 4.6-4.7 (m, 1H), 4.6-4.7 (m, 1H), 4.3-4.4 (m, 1H), 3.8-4.1 (m, 4H), 3.4-3.6 (m, 2H), 2.67 (s, 1H), 2.6-2.7 (m, 1H), 2.5-2.8 (m, 1H), 2.2-2.3 (m, 1H), 2.1-2.5 (m, 6H), 1.8-1.9 (m, 1H), 1.3-1.4 (m, 1H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 8.98 - 9.05 (m, 1 H), 7.64 - 7.74 (m, 1 H), 7.30 - 7.33 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.00 - 7.07 (m, 1 H), 5.46 - 5.67 (m, 1 H), 4.97 - 5.11 (m, 1 H), 19 580.2 4.56 -4.73 (m, 4 H), 4.19 -4.32 (m, 1 H), 3.81 -4.08 (m, 4 H), 3.41 - 3.53 (m, 1 H), 2.29 - 2.78 (m, 9 H), 2.09 - 2.23 (m, 2 H), 0.74 - 0.84 (m, 3 H).
- 183 -E MS
x.
m/z (ESI): 11-1 NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 8.92 - 9.02 (m, 1 H), 7.63 - 7.73 (m, 1 H), 7.30 - 7.33 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.01 -7.07 (m, 1 H), 5.47 - 5.67 (m, 1 H), 5.33 - 5.44 (m, 1 H), 20 592.2 4.89 - 5.02 (m, 1 H), 4.44 - 4.72 (m, 5 H), 3.80 - 4.28 (m, 4 H), 3.42 - 3.72 (m, 4 H), 2.27 - 2.78 (m, 6 H), 2.09 - 2.22 (m, 2 H), 0.74 - 0.86 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 8.94 - 9.20 (m, 1 H), 7.63 - 7.72 (m, 1 H), 7.30 - 7.35 (m, 1 H), 7.21 - 7.29 (m, 1 H), 21 592.2 6.99 - 7.07 (m, 1 H), 5.49 - 5.68 (m, 1 H), 5.02 -5.15 (m, 1H), 4.61 -4.73 (m, 4 H), 3.79 - 4.39 (m, 6 H), 3.42 - 3.56 (m, 1H), 2.29 - 2.78 (m, 8 H), 2.09 - 2.24 (m, 2 H), 0.74 - 0.84 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.17 - 9.26 (m, 1 H), 7.64 - 7.74 (m, 1 H), 7.31 - 7.34 (m, 1 H), 7.23 - 7.29 (m, 1 H), 7.02 - 7.09 (m, 1 H), 5.49 - 5.68 (m, 1 H), 4.64 - 4.79 (m, 2 H), 22 656.1 4.14 - 4.30 (m, 2 H), 3.84 - 4.10 (m, 5 H), 3.62 -3.77 (m, 2 H), 3.53 - 3.60 (m, 2 H), 3.42 - 3.53 (m, 1 H), 2.53 - 2.83 (m, 2 H), 2.28 -2.50 (m, 4 H), 2.10 - 2.27 (m, 2 H), 1.72- 1.97 (m, 4 H), 0.74 - 0.85 (m, 3 H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.31 (d, 1H, J=18.4 Hz), 7.70 (dd, 1H, J=6.0, 8.9 Hz), 7.34 (d, 1H, J=2.7 Hz), 7.27 (t, 1H, J=9.3 Hz), 7.08 (dd, 1H, J=2.5, 15.0 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 23 620.3 (m, 3H), 4.37 (qd, 1H, J=5.0, 10.2 Hz), 3.8-4.1 (m, 4H), 3.4-3.6 (m, 2H), 2.6-2.8 (m, 2H), 2.1-2.5 (m, 9H), 1.9-2.0 (m, 1H), 1.84 (br d, 1H, J=9.6 Hz), 1.37 (br dd, 1H, J=2.6, 13.7 Hz), 0.8-0.9 (m, 3H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.31 (d, 1H, J=18.4 Hz), 7.70 (dd, 1H, J=6.0, 8.9 Hz), 7.34 (d, 1H, J=2.7 Hz), 7.27 (t, 1H, J=9.3 Hz), 7.08 (dd, 1H, J=2.5, 15.0 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 24 620.3 (m, 3H), 4.37 (qd, 1H, J=5.0, 10.2 Hz), 3.8-4.1 (m, 4H), 3.4-3.6 (m, 2H), 2.6-2.8 (m, 2H), 2.1-2.5 (m, 9H), 1.9-2.0 (m, 1H), 1.84 (br d, 1H, J=9.6 Hz), 1.37 (br dd, 1H, J=2.6, 13.7 Hz), 0.8-0.9 (m, 3H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.31 (d, 1H, J=18.4 Hz), 7.70 (dd, 1H, J=6.0, 8.9 Hz), 7.34 (d, 1H, J=2.7 Hz), 7.27 (t, 1H, J=9.3 Hz), 7.08 (dd, 1H, J=2.5, 15.0 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 25 620.3 (m, 3H), 4.37 (qd, 1H, J=5.0, 10.2 Hz), 3.8-4.1 (m, 4H), 3.4-3.6 (m, 2H), 2.6-2.8 (m, 2H), 2.1-2.5 (m, 9H), 1.9-2.0 (m, 1H), 1.84 (br d, 1H, J=9.6 Hz), 1.37 (br dd, 1H, J=2.6, 13.7 Hz), 0.8-0.9 (m, 3H).
- 184 -E MS
x.
m/z (ESI): 11-1 NMR
(M+H)+
IHNMR (METHANOL-d4, 400 MHz) 6 9.31 (d, 1H, J=18.4 Hz), 7.70 (dd, 1H, J=6.0, 8.9 Hz), 7.34 (d, 1H, J=2.7 Hz), 7.27 (t, 1H, J=9.3 Hz), 7.08 (dd, 1H, J=2.5, 15.0 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 26 620.3 (m, 3H), 4.37 (qd, 1H, J=5.0, 10.2 Hz), 3.8-4.1 (m, 4H), 3.4-3.6 (m, 2H), 2.6-2.8 (m, 2H), 2.1-2.5 (m, 9H), 1.9-2.0 (m, 1H), 1.84 (br d, 1H, J=9.6 Hz), 1.37 (br dd, 1H, J=2.6, 13.7 Hz), 0.8-0.9 (m, 3H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.31-9.16 (m, 1H), 7.8-7.9 (m, 1H), 7.2-7.4 (m, 3H), 5.5-5.7 (m, 1H), 5.1-5.3 (m, 1H), 27 616.3 4.6-4.7 (m, 2H), 4.2-4.4 (m, 1H), 3.8-4.1 (m, 4H), 3.4-3.5 (m, 3H), 2.6-2.7 (m, 2H), 2.1-2.5 (m, 7H), 1.9-2.0 (m, 1H), 1.8-1.9 (m, 1H), 1.3-1.4 (m, 2H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.31-9.16 (m, 1H), 7.8-7.9 (m, 1H), 7.2-7.4 (m, 3H), 5.5-5.7 (m, 1H), 5.1-5.3 (m, 1H), 28 616.3 4.6-4.7 (m, 2H), 4.2-4.4 (m, 1H), 3.8-4.1 (m, 4H), 3.4-3.5 (m, 3H), 2.6-2.7 (m, 2H), 2.1-2.5 (m, 7H), 1.9-2.0 (m, 1H), 1.8-1.9 (m, 1H), 1.3-1.4 (m, 2H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.29 (d, 1H, J=9.8 Hz), 7.65 (d, 1H, J=8.2 Hz), 7.3-7.4(m, 2H), 7.18 (d, 1H, J=7.3 Hz), 29 602.2 7.03 (dd, 1H, J=2.6, 13.9 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 (m, 3H), 4.36 (br dd, 1H, J=5.1, 9.7 Hz), 3.8-4.1 (m, 4H), 3.4-3.6 (m, 2H), 2.5-2.8 (m, 2H), 2.1-2.5 (m, 10H), 1.8-2.0 (m, 2H), 1.3-1.4 (m, 1H), 0.91 (q, 3H, J=7.1 Hz).
IHNMR (METHANOL-d4, 400 MHz) 6 9.30 (s, 1H), 7.00 (d, 1H, J=2.7 Hz), 6.82 (d, 1H, J=2.5 Hz), 5.5-5.7 (m, 1H), 4.35 (td, 1H, 30 598.2 J=5.3, 10.2 Hz), 3.7-4.1 (m, 5H), 3.4-3.6 (m, 2H), 2.5-2.8 (m, 3H), 2.1-2.5 (m, 8H), 1.9-2.0 (m, 1H), 1.8-1.9 (m, 2H), 1.3-1.4 (m, 2H), 0.5-0.7 (m, 2H), 0.0-0.2 (m, 2H).
1H NMR (METHANOL-d4, 400 MHz) 6 9.1-9.3 (m, 1H), 7.85 (br d, 1H, J=7.1 Hz), 7.5-7.6 (m, 1H), 7.3-7.5 (m, 2H), 7.2-7.3 (m, 31 598.2 1H), 5.6-5.7 (m, 1H), 5.21 (br d, 1H, J=12.3 Hz), 4.6-4.7 (m, 2H), 4.35 (dt, 1H, J=5.6, 10.7 Hz), 3.8-4.1 (m, 5H), 3.4-3.6 (m, 2H), 2.5-2.8 (m, 3H), 2.1-2.5 (m, 8H), 1.8-2.0 (m, 2H).
IHNMR (METHANOL-d4, 400 MHz) 6 9.28 (br d, 1H, J=14.2 Hz), 7.71 (dd, 1H, J=5.9, 8.8 Hz), 7.2-7.4 (m, 2H), 7.10 (dd, 1H, 32 622.3 J=2.2, 7.8 Hz), 5.5-5.7 (m, 1H), 4.69 (br s, 1H), 4.5-4.7 (m, 2H), 3.8-4.3 (m, 5H), 3.4-3.6 (m, 3H), 2.6-2.9 (m, 2H), 2.3-2.5 (m, 4H), 2.21 (br d, 2H, J=6.1 Hz), 1.9-2.0 (m, 1H), 1.5-1.7 (m, 1H), 1.15 (br d, 3H, J=4.6 Hz), 0.9-1.1 (m, 3H), 0.82 (br t, 3H, J=7.2 Hz).
- 185 -MS
Ex.
m/z (ESI): 111 NMR
(M+H)+
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.09 (s, 1 H), 7.70 (dd, J=9.1, 5.7 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.08 (dd, J=9.0, 2.7 Hz, 1 H), 5.52 - 5.71 (m, 1 H), 4.99 33 608.2 - 5.11 (m, 1 H), 4.58 - 4.67 (m, 2 H), 3.83 - 4.11 (m, 4 H), 3.45 -3.56 (m, 1 H), 2.67 (s, 2 H), 2.32 - 2.63 (m, 5 H), 1.78 - 2.29 (m, 7 H), 1.59 (dd, J=6.9, 1.9 Hz, 3 H), 0.82 (dt, J=10.9, 7.4 Hz, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.19 (s, 1 H), 7.70 (dd, J=9.1, 5.7 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (d, J=2.5 Hz, 1 H), 5.51 - 5.68 (m, 1 H), 5.24 - 5.37 34 620.4 (m, 1 H), 5.09 - 5.20 (m, 1 H), 4.67 (br d, J=2.5 Hz, 2 H), 3.82 -4.13 (m, 4 H), 3.46 - 3.55 (m, 1 H), 2.72 -2.81 (m, 1 H), 2.60 (s, 1 H), 2.43 - 2.54 (m, 2 H), 2.34 - 2.42 (m, 2 H), 2.15 - 2.31 (m, 4 H), 1.91 -2.11 (m, 4 H), 1.70- 1.90 (m, 2 H), 0.83 (t, J=7.2 Hz, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.17 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (t, J=2.4 Hz, 1 H), 5.53 - 5.74 (m, 1 H), 4.66 (br d, 35 608.2 J=1.5 Hz, 2H), 3.86 -4.13 (m, 3 H), 3.43 - 3.64 (m, 4 H), 2.67-2.82 (m, 2 H), 2.56 -2.66 (m, 1 H), 2.31 -2.53 (m, 5 H), 2.13 -2.26 (m, 2 H), 2.00 - 2.10 (m, 1 H), 1.78 (dtt, J=8.7, 6.5, 6.5, 4.5, 4.5 Hz, 1 H), 1.42 - 1.59 (m, 1 H), 1.15 - 1.22 (m, 3 H), 0.82 (td, J=7.3, 4.2 Hz, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.40 - 9.50 (m, 1 H), 7.68 - 7.72 (m, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.25 - 7.30 (m, 1 H), 7.05 - 7.09 (m, 1 H), 5.49 - 5.71 (m, 2 H), 4.61 - 4.72 (m, 2 H), 36 608.2 3.91 (br d, J=17.3 Hz, 4 H), 3.50 (br dd, J9.4, 5.4 Hz, 1 H), 2.69 - 2.81 (m, 1 H), 2.61 (br d, J=4.4 Hz, 1 H), 2.45 -2.52 (m, 3 H), 2.31 - 2.42 (m, 4H), 2.16 - 2.28 (m, 4H), 1.49- 1.54(m, 3 H), 0.82 (t, J=7.3 Hz, 4 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.35 (d, J=3.3 Hz, 1 H), 7.71 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, 37 606.3 J=9.4 Hz, 1 H), 7.07 (t, J=3.1 Hz, 1 H), 5.48 - 5.70 (m, 1 H), 4.64 - 4.75 (m, 4 H), 4.23 - 4.49 (m, 3 H), 3.83 - 4.04 (m, 5 H), 3.45 -3.58 (m, 1 H), 3.20 - 3.29 (m, 1 H), 2.71 -2.81 (m, 1 H), 2.04 -2.67 (m, 11 H), 0.72 -0.88 (m, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.31 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.07 (t, J=2.4 Hz, 1 H), 5.48 - 5.72 (m, 1 H), 4.69 (s, 3 38 608.4 H), 4.38 (br t, J=12.0 Hz, 1 H), 3.84 -4.14 (m, 3 H), 3.60 - 3.72 (m, 1 H), 3.43 - 3.56 (m, 2 H), 2.70 -2.82 (m, 1 H), 2.56 - 2.66 (m, 1 H), 2.34 - 2.51 (m, 4 H), 2.13 -2.30 (m, 3 H), 1.77- 1.94 (m, 3 H), 1.32 (d, J=7.9 Hz, 3 H), 0.78 - 0.89 (m, 3 H).
- 186 -E MS
x.
m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.27 - 9.36 (m, 1 H), 7.66 -7.75 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.05 -7.11 (m, 1 H), 5.50 - 5.98 (m, 2 H), 4.66 -4.76 (m, 3 H), 39 644.0 4.52 - 4.63 (m, 1 H), 3.83 -4.12 (m, 3 H), 3.68 - 3.81 (m, 1 H), 3.42 - 3.55 (m, 2 H), 2.54 - 2.83 (m, 2 H), 2.32 - 2.53 (m, 4 H), 2.13 -2.30 (m, 3 H), 1.85 -2.08 (m, 3 H), 0.82 (d, J=7.1 Hz, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.27 - 9.36 (m, 1 H), 7.66 -7.75 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.05 -7.11 (m, 1 H), 5.50 - 5.97 (m, 2 H), 4.64 -4.76 (m, 3 H), 40 644.0 4.52 - 4.63 (m, 1 H), 3.83 -4.11 (m, 3 H), 3.68 - 3.81 (m, 1 H), 3.42 - 3.56 (m, 2 H), 2.54 - 2.81 (m, 2 H), 2.31 - 2.51 (m, 4 H), 2.12 -2.29 (m, 3 H), 1.87 - 2.05 (m, 3 H), 0.82 (br d, J=3.8 Hz, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.19 (s, 1 H), 7.85 -7.93 (m, 1 H), 7.40 (d, J=2.5 Hz, 1 H), 7.31 - 7.38 (m, 1 H), 7.25-41 640.2 7.31 (m, 1 H), 5.48 - 5.98 (m, 2 H), 4.66 -4.77 (m, 3 H), 4.51 -4.64 (m, 1 H), 3.86 - 4.10 (m, 3 H), 3.74 - 3.86 (m, 1 H), 3.50 (br d, J=0.8 Hz, 3 H), 2.55 -2.82 (m, 2 H), 2.31 -2.51 (m, 3 H), 2.10 -2.30 (m, 2 H), 1.80 - 2.07 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 8.95 - 9.25 (m, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.23 - 7.46 (m, 2 H), 7.07 (dd, J=10.7, 2.5 Hz, 1 H), 5.34 - 5.73 (m, 1 H), 5.12 - 5.29 (m, 1 H), 42 620.0 4.61 -4.77 (m, 3 H), 4.18 -4.45 (m, 2 H), 3.74 -4.03 (m, 5 H), 3.40 -3.64 (m, 1 H), 2.56 -2.92 (m, 3 H), 2.41 -2.55 (m, 2 H), 2.10 - 2.41 (m, 6 H), 1.98 - 2.15 (m, 3 H), 1.78- 1.93 (m, 1 H), 0.73 - 0.92 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.60 - 9.73 (m, 1 H), 7.71 (s, 2 H), 7.36 (d, J=2.5 Hz, 1 H), 7.28 -7.34 (m, 1 H), 7.14 (d, J=2.5 Hz, 1 H), 5.51 - 5.76 (m, 1 H), 4.90 -4.95 (m, 1 H), 4.72 170 590.0 - 4.84 (m, 2 H), 4.39 - 4.55 (m, 1 H), 3.81 - 4.07 (m, 3 H), 3.57 -3.73 (m, 1 H), 3.39 - 3.55 (m, 2 H), 2.56 -2.84 (m, 2 H), 2.32 -2.55 (m, 4 H), 2.11 -2.32 (m, 3 H), 1.77- 1.98 (m, 3 H), 1.36 (s, 3 H), 0.90 (t, J=7.4 Hz, 3 H) 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.29 - 9.36 (m, 1 H), 7.66 -7.76 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.23 - 7.31 (m, 1 H), 171 626.0 7.05 -7.12 (m, 1 H), 5.49 - 5.72 (m, 1 H), 4.60 -4.79 (m, 3 H), 4.39 -4.53 (m, 2 H), 4.25 - 4.38 (m, 1 H), 3.78 - 4.15 (m, 4 H), 3.42 - 3.66 (m, 2 H), 2.55 - 2.83 (m, 2 H), 2.31 - 2.53 (m, 4 H), 2.09 -2.29 (m, 3 H), 1.78 - 1.98 (m, 3 H), 0.75 - 0.89 (m, 3 H)
- 187 -MS
Ex.
m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.28 - 9.38 (m, 1 H), 7.65 -7.77 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.25 - 7.31 (m, 1 H), 172 626.0 7.02 - 7.13 (m, 1 H), 5.48 - 5.71 (m, 1 H), 4.57 -4.81 (m, 3 H), 4.39 -4.52 (m, 2 H), 4.25 - 4.38 (m, 1 H), 3.77 - 4.14 (m, 4 H), 3.42 - 3.67 (m, 2 H), 2.54 - 2.84 (m, 2 H), 2.31 - 2.54 (m, 4 H), 2.12 -2.30 (m, 3 H), 1.75 - 1.98 (m, 3 H), 0.75 - 0.89 (m, 3 H) 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.34 (s, 1 H), 6.44 -6.75 (m, 2 H), 5.28 - 5.83 (m, 1 H), 4.53 - 4.76 (m, 3 H), 4.24 -173 594.4 4.41 (m, 1 H), 3.83 - 4.17 (m, 3 H), 3.39 - 3.74 (m, 3 H), 2.53 -2.93 (m, 5 H), 2.29 - 2.50 (m, 3 H), 2.06 - 2.26 (m, 2 H), 1.67 -1.95 (m, 7 H), 1.32 (s, 5 H), 0.33 - 0.60 (m, 3 H) 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.06 - 9.26 (m,1 H), 6.35 -6.83 (m, 2 H), 5.10 - 5.55 (m, 1 H), 4.46 -4.60 (m, 1 H), 174 594.4 4.10 - 4.38 (m, 3 H), 3.56 - 3.72 (m, 1 H), 3.39 -3.53 (m, 1 H), 3.14 - 3.28 (m, 3 H), 2.99 - 3.10 (m, 1 H), 2.69 - 2.89 (m, 3 H), 2.07 -2.41 (m, 5 H), 1.67 -2.06 (m, 12 H), 1.02 - 1.50 (m, 2 H), 0.41 -0.64 (m, 3 H) 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.14 - 9.38 (m, 1 H), 6.49 -6.90 (m, 2 H), 5.44 - 5.78 (m, 1 H), 5.09 - 5.33 (m, 1 H), 175 606.0 5.04 - 5.29 (m, 1 H), 4.83 - 4.97 (m, 1 H), 4.55 -4.76 (m, 4 H), 4.27 - 4.41 (m, 1 H), 3.80 - 4.13 (m, 3 H), 3.37 - 3.71 (m, 4 H), 2.53 -2.98 (m, 4 H), 2.31 - 2.48 (m, 3 H), 2.09 - 2.29 (m, 2 H), 1.55 - 1.95 (m, 7 H), 1.28 - 1.35 (m, 6 H) 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide (Example 43)
- 188 -o ¨t)LNH2 0,13 ¨t)cH2 N HCI
1. 'Pr2NEt CH3CN
N N __________________________ Os' HO14, N \
CI N CI CI I N 0 cataCXium A Pd G3 2. THF/H20 Step l Step 2 Ay'Lls,1H2 F HCI in 1,4-Dioxane N N N
N 0 MeCN N 0 .00 Step 3 Example 43 Step 1: 1-(7-Chloro-8-fluoro-2-1((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide.
To a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-dlpyrimidine (0.10 g, 0.40 mmol, .. LabNetwork) in acetonitrile (2.0 mL) at 0 C was added 5,5-dimethylpiperidine-3-carboxamide hydrochloride (80 mg, 0.42 mmol, Intermediate Gl) and DIPEA (0.21 mg, 0.28 mL, 1.58 mmol, Aldrich). The reaction was stirred at 0 C. Separately, a solution of 42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.11 g, 0.71 mmol, Labnetwork) in acetonitrile (1.0 mL) was dried over anhydrous magnesium sulfate. The mixture was stirred for 5 minutes at rt temperature, and then filtered through celite to remove the magnesium sulfate. After 20 minutes, (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide) was observed. Two mixtures were combined and the reaction was stirred at 80 C overnight. The reaction was cooled to rt and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100 % 3:1 Et0AciEt0H (with 2% triethylamine) in heptane to provide 1-(7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
- 189 -yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide (0.12 g, 0.24 mmol, 61 % yield) as orange solid. m/z (ESI): 495.0 (M+H)+.
Step 2: 1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yOmethoxy)pyrido14,3-d]pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide. A 1 dram vial was charged with 1-(7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(511)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide (50 mg, 0.10 mmol), 2-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (55 mg, 0.15 mmol, PharmaBlock), potassium phosphate (64 mg, 0.30 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (0.09 mL). The reaction was then sealed and stirred at 65 C overnight. The reaction was then cooled to rt and concentrated under reduced pressure to afford a crude black oil. The oil was then purified via column chromatography on silica gel, eluting with a gradient of 0-100% 3:1 Et0AciEt0H (with 2%
triethylamine) in heptane to provide 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol, 85 % yield) as off-white solid.
m/z (ESI): 693.2 (M+H)+.
Step 3: 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)pyrido[4,3-d]pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide. 1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol) was dissolved in MeCN (3.1 mL) and HC1 (4 M in 1,4-dioxane,0.6 mL, 2.53 mmol, Sigma-Aldrich Corporation). The reaction was stirred at rt for 3 h then cooled to rt and concentrated under reduced pressure to provide a crude orange oil. The oil was then purified by reverse phase HPLC to provide 1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide 2,2,2-trifluoroacetate (38 mg, 0.05 mmol, 49 % yield) as light-yellow solid. m/z (ESI): 649.2 (M+H)+. 1HNMR (400 MHz,
- 190 -METHANOL-d4) 6 ppm 9.19 (s, 1 H), 7.65 - 7.75 (m, 1 H), 7.31 - 7.36 (m, 1 H), 7.23 - 7.30 (m, 1 H), 7.04 - 7.13 (m, 1 H), 5.49 - 5.71 (m, 1 H), 4.65 -4.77 (m, 3 H), 4.36 -4.49 (m, 1 H), 3.82 - 4.12 (m, 3 H), 3.35 - 3.54 (m, 3 H), 2.98 - 3.14 (m, 1 H), 2.54 -2.86 (m, 2 H), 2.32 -2.53 (m, 4 H), 2.14 - 2.30 (m, 2 H), 1.73 - 1.95 (m, 2 H), 1.12 (d, J=4.0 Hz, 3 H), 0.96 -1.09 (m, 3 H), 0.73 -0.87 (m, 3 H).
Table 5. Examples 44 to 72. Prepared in an analogous manner to Example 43.
Ex. Salt Method Structure Name Reagent Form Change 44 c.j.NH2 4-(4-((R)-3- bis(2, Step 1: (R)-Addition Aminopiperidin- 2,2- tert-butyl al step F 1-y1)-8-fluoro-2- trifluo piperidin-3- between I (((2R,7aS)-2- roacea ylcarbamate Step 1 N fluorotetrahydro- te) (CAS#: and Step OH 1H-pyrrolizin- 309956-78-3, 2. Details 7a(511)- Ambeed, included yl)methoxy)pyrid Inc.) below.
o[4,3-d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen -2-ol ) 4-(4-((S)-3- bis(2, Step 1: tert-Addition Amino-3- 2,2- butyl N- al step methylpiperidin- trifluo R35)-3- analogou N ===== N
1-y1)-8-fluoro-2- roacea methylpiperi s to N*Lc)6---SN (((2R,7aS)-2- te) din-3- Example fluorotetrahydro- ylicarbamate 44.
OH
1H-pyrrolizin- (CAS#:
7a(5H)- 1363378-21-yl)methoxy)pyrid 5, o[4,3- Pharmablock al pyrimidin-7- , Inc.) y1)-5-ethy1-6-fluoronaphthalen -2-ol
- 191 -Ex. Salt Method Structure Name Reagent Form Change 4-(4-((R)-3- bis(2, Step 1: tert-Addition Cf Amino-3- 2,2- butyl N- al step methylpiperidin- trifluo [(3R)-3- analogou N==== ==== N
*Lo 1-y1)-8-fluoro-2- roacea methylpiperi s to (((2R,7aS)-2- te) din-3- Example fluorotetrahydro- ylicarbamate 44.
OH
1H-pyrrolizin- (CAS#:
7a(5H)- 1169762-18-yl)methoxy)pyrid 8, o[4,3- Pharmablock al pyrimidin-7- , Inc.) y1)-5-ethy1-6-fluoronaphthalen -2-ol 47 (3R,45)-1-(7-(8- bis(2, Step 1:
aoou Ethyl-7-fluoro-3- 2,2- (3R,45)-4-hydroxynaphthal trifluo fluoropiperid en-1-y1)-8- roacet in-3-ol (10 N1 N)os fluoro-2- ate) hydrochlorid F N (42R,7aS)-2- e (CAS#:
fluorotetrahydro- 1638765-12-OH
1H-pyrrolizin- 4, 7a(5H)- Accelerate) yl)methoxy)pyrid o[4,3-al pyrimidin-4-y1)-4-fluoropiperidin-3-ol 48 dOH (R)-1-(7-(8- 2,2,2-Step 1: (3R)- No Step Ethyl-7- trifluo 3- 3 fluoronaphthalen roacea methylpiperi N N -1-y1)-8-fluoro-2- te din-3-ol (42R,7aS)-2- hydrochlorid fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 2305080-34-7a(5H)- 4, yl)methoxy)pyrid Pharmablock o[4,3-al pyrimidin-4-y1)-3- Step 2: 2-(8-methylpiperidin- ethy1-7-3-ol fluoronaphth
- 192 -Ex. Salt Method Structure Name Reagent Form Change alen-l-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (Intermediat e B) 49 CJ' (R)-1-(7-(7,8- 2,2,2- Step 1:
(3R)- No Step Difluoronaphthal trifluo 3- 3 en-1-y1)-8- roacea methylpiperi (10 \ fluoro-2- te din-3-ol (42R,7aS)-2- hydrochlorid *F N*LV114 N
fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 2305080-34-7a(511)- 4, yl)methoxy)pyrid Pharmablock ol4,3-al pyrimidin-4-y1)-3- Step 2: 2-methylpiperidin- (7,8-3-01 difluoronapht halen-l-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (CAS#:

6, LabNetwork) 50 dON (R)-1-(7-(8- 2,2,2-Step 1: (3R)- No Step Ethyny1-7- trifluo 3- 3.
fluoronaphthalen roacea methylpiperi N N -1-y1)-8-fluoro-2- te din-3-ol Addition N N (42R,7aS)-2- hydrochlorid al step fluorotetrahydro- e (CAS#: analogou 1H-pyrrolizin- 2305080-34- s to 7a(5H)- 4, Example yl)methoxy)pyrid Pharmablock 27 after ol4,3- Step 2.
al pyrimidin-4-y1)-3-
- 193 -Ex. Salt Method Structure Name Reagent Form Change methylpiperidin- Step 2: ((2-3-ol fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)naphthalen yl)e thynyl)tri isopropylsila ne (CAS#:

5, LabNetwork) 51 2-(7-(8-Ethy1-7- 2,2,2- Step 1: 2-fluoro-3- trifluo azabicyc1o[2.
F hydroxynaphthal roacea 2.1]heptan-6-N"=%. ==== N
I en-1-y1)-8- te ol N fluoro-2- hydrochlorid (42R,7aS)-2- e (CAS#:
OH
fluorotetrahydro- 2007916-89-1H-pyrrolizin- 2, AstaTech, 7a(511)- Inc) yl)methoxy)pyrid o[4,3-d] pyrimidin-4-y1)-2-azabicyclo[2.2.1]
heptan-6-ol rt"" (R)-1-(7-(8- bis(2, Step 1: (3R)- Addition Ethyny1-7-fluoro- 2,2- 3- al step 3- trifluo methylpiperi analogou 1\11 hydroxynaphthal roacet din-3-ol s to en-1-y1)-8- ate) hydrochlorid Example fluoro-2- e (CAS#: 27 after OH (((2R,7aS)-2- 2305080-34-Step 3.
fluorotetrahydro- 4), 1H-pyrrolizin- Synnovator) 7a(5H)-yl)methoxy)pyrid Step 2: 247-o[4,3- fluoro-3-d]pyrimidin-4- (methoxymet
- 194 -Ex. Salt Method Structure Name Reagent Form Change hoxy)-8-[2-methylpiperidin- [tris(1-3-ol methylethyl)s ilyllethynyll-naphthalenyl]
-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (CAS#:

2, LabNetwork) (R)-1-(7-(8-ethyl- 2,2,2- Step 1: (3R)-7-fluoro-3- trifluo 3-F N hydroxynaphthal roacet methylpiperi N en-1-y1)-8- ate din-3-ol N

fluoro-2- hydrochlorid (((2R,7aR)-2- e (CAS#:
OH fluorotetrahydro- 2305080-34-1H-pyrrolizin- 4, 7a(511)- Pharmablock yl)methoxy)pyrid ); ((2R,7aR)-o[4,3- 2-al pyrimidin-4- fluorotetrahy y1)-3- dro-1H-methylpiperidin- pyrrolizin-3-ol 7a(5H)-yl)methanol (CAS#:

3, LabNetwork)
- 195 -Ex. Salt Method Structure Name Reagent # Form Change 1-(7-(8-Ethy1-7- bis(2, Step 1: Chiral fluoro-3- 2,2- azepane-4- separatio hydroxynaphthal trifluo carbonitrile n after F N en-1-y1)-8- roacet hydrochlorid Step 1.
N s'''= 1\1 F fluoro-2- ate) e (CAS#: Details I NO,6____s (((2R,7a5)-2- 1259062-50- included F N fluorotetrahydro- 4, AstaTech below.
OH 1H-pyrrolizin- Inc.) 7a(511)-yl)methoxy)pyrid o[4,3-al pyrimidin-4-yl)azepane-4-carbonitrile Isomer 1 1-(7-(8-Ethy1-7- bis(2, Step 1: Chiral fluoro-3- 2,2- azepane-4- separatio ,N) hydroxynaphthal trifluo carbonitrile n after F en-1-y1)-8- roacet hydrochlorid Step 1.
N 1\1 F fluoro-2- ate) e (CAS#: Details I
NI-0--6--S (((2R,7a5)-2- 1259062-50- included F N fluorotetrahydro- 4, AstaTech below.
OH 1H-pyrrolizin- Inc.) 7a(5H)-yl)methoxy)pyrid o[4,3-al pyrimidin-4-yl)azepane-4-carbonitrile Isomer 2
- 196 -Ex. Salt Method Structure Name Reagent Form Change 56 040H (R)-1-(7-(8- bis(2, Step 1:
(3R)-N F Chloro-7-fluoro- 2,2- 3-F. r\ NCI 3- trifluo methylpiperi V
N
hydroxynaphthal roacet din-3-ol en-1-y1)-8-fluoro-2- ate) hydrochlorid e (CAS#:
OH (((2R,7aS)-2- 2305080-34-fluorotetrahydro- 4), 1H-pyrrolizin- Synnovator) 7a(5H)-yl)methoxy)pyrid Step 2: 2-(8-o[4,3- chloro-7-al pyrimidin-4- fluoro-3-y1)-3- (methoxymet methylpiperidin- hoxy)naphtha 3-ol len-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (Intermediat e 0) 57 -Z=OH (R)-1-(8-Fluoro- bis(2, Step 1: (3R)-7-(8-fluoro-3- 2,2- 3-F. r\ N hydroxynaphthal trifluo methylpiperi V
en-1-y1)-2- roacet din-3-ol N
(((2R,7aS)-2- ate) hydrochlorid fluorotetrahydro- e (CAS#:
OH 1H-pyrrolizin- 2305080-34-7a(5H)- 4), yl)methoxy)pyrid Synnovator) o[4,3-al pyrimidin-4- Step 2: 2-(8-y1)-3- fluoro-3-methylpiperidin- (methoxymet 3-01 hoxy)naphtha len-l-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (CAS#:
- 197 -Ex. Salt Method Structure Name Reagent Form Change 0, LabNetwork) 58 n4OH (R)-1-(7-(8- 2,2,2- Step 1:
(3R)-N
Ethyl-3- trifluo 3-hydroxynaphthal roacet methylpiperi N
c770 N I en-1-y1)-8- ate din-3-ol fluoro-2-(42R,7aS)-2- hydrochlorid e (CAS#:
H fluorotetrahydro- 2305080-34-1H-pyrrolizin- 4), 7a(511)- Synnovator) yl)methoxy)pyrid o[4,3- Step 2: 2-(8-dlpyrimidin-4- ethyl-3-y1)-3- (methoxymet methylpiperidin- hoxy)naphtha 3-ol len-1-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (CAS#:

1, LabNetwork) 59 040H (R)-1-(7-(7,8- bis(2, Step 1:
(3R)-N F Difluoro-3- 2,2- 3-F. r\ N hydroxynaphthal trifluo methylpiperi V
en-1-y1)-8- roacet din-3-ol N
fluoro-2-(42R,7aS)-2- ate) hydrochlorid e (CAS#:
H fluorotetrahydro- 2305080-34-1H-pyrrolizin- 4), 7a(511)- Synnovator) yl)methoxy)pyrid o[4,3- Step 2: 2-al pyrimidin-4- (7,8-difluoro-y1)-3- 3-methylpiperidin- (methoxymet 3-01 hoxy)naphtha len-l-y1)-4,4,5,5 -
- 198 -Ex. Salt Method Structure Name Reagent Form Change tetramethyl-1,3,2-dioxaborolan e (CAS#:

9, LabNetwork) 60 (R)-1-(8-Fluoro- 2,2,2-Step 1: (3R)- No Step 2-(42R,7aS)-2- trifluo 3- 3 fluorotetrahydro- roacet methylpiperi 1H-pyrrolizin- ate din-3-ol N 7a(511)- hydrochlorid yl)methoxy)-7- e (CAS#:
OH (3- 2305080-34-hydroxynaphthal 4), en-1- Synnovator) yl)pyrido[4,3-cilpyrimidin-4- Step 2: 3-y1)-3- hydroxynaph methylpiperidin- thalene-1-3-ol boronicacid (CAS#:

1, Angel Pharmatech Ltd.) 61 rel-(3aR,6aS)-5- bis(2, Step 1: rac-c).}
(7-(8-Ethyl-7- 2,2- (3aR,6aS)-fluoro-3- trifluo octahydropyr hydroxynaphthal roacet rolo[3,4-F
N en-1-y1)-8- ate) clpyrrol-1-fluoro-2- one (42R,7aS)-2- hydrochlorid OH fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 2206134-91-7a(5H)- 8, Enamine) yl)methoxy)pyrid o[4,3-alpyrimidin-4-yl)hexahydropyrr olo[3,4-clpyrrol-1(211)-one
- 199 -Ex. Salt Method Structure Name Reagent Form Change 62 5-Ethyl-6-fluoro- 2,2,2- Step 1: rac-4-(8-fluoro-2- trifluo (3aR,7aS)--- (42R,7aS)-2- roacet octahydrofur N 1\1 F fluorotetrahydro- ate o[3,2-N 0 1H-pyrrolizin- clpyridine 7a(5H)- hydrochlorid yl)methoxy)-4- e (CAS#:
OH
re1-((3aR,7aS)- 1629784-77-hexahydrofuro[3, 5, Enamine) 2-clpyridin-5(4H)-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 63 rel-(3aR,7aR)-4- 2,2,2- Step 1:
rac-o (7-(8-Ethyl-7- trifluo (3aR,7aR)-F N
F fluoro-3- roacet octahydro-hydroxynaphthal ate 1H-N'0" N en-1-y1)-8- pyrrolo[3,2-fluoro-2- blpyridin-2-OH (42R,7aS)-2- one fluorotetrahydro- hydrochlorid 1H-pyrrolizin- e (CAS#:
7a(5H)- 2241129-83-yl)methoxy)pyrid 7, Enamine) o[4,3-al pyrimidin-4-yl)octahydro-2H-pyrrolo[3,2-b] pyridin-2-one
- 200 -Ex. Salt Method Structure Name Reagent Form Change 64 NH2 rel-(3S,6R)-1-(7- 2,2,2- Step 1:
rac-Xo (8-Ethyl-7- trifluo (3R,65)-6-F fluoro-3- roacet methylpiperi N r\J F hydroxynaphthal ate dine-en-1-y1)-8- carboxamide NO'6-7\
fluoro-2- hydrochlorid (42R,7aS)-2- e (CAS#:
OH
fluorotetrahydro- 2241141-04-1H-pyrrolizin- 6, Enamine) 7a(5H)-yl)methoxy)pyrid o[4,3-d]pyrimidin-4-y1)-6-methylpiperidine -3-carboxamide 65 cf\OH 3-Ethy1-1-(7-(8- bis(2, Step 1: 3-ethy1-7-fluoro-3- 2,2- ethylpiperidi hydroxynaphthal trifluo 11-3-ol en-1-y1)-8- roacet (CAS#:
fluoro-2- ate) 1177299-74-N
(((2R,7aS)-2- 9, Enamine) OH fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrid o[4,3-d]pyrimidin-4-yl)piperidin-3-ol 66 -OH 5-Ethyl-6-fluoro- 2,2,2- Step 1: [(35)-4-(8-fluoro-2- trifluo 3-F (42R,7aS)-2-roacet methylpiperi N fluorotetrahydro- ate din-3-N*Lo'"'= 1H-pyrrolizin- yl]methanol 7a(5H)- hydrochlorid OH yl)methoxy)-4- e (CAS#:
((5)-3- 1956435-41-(hydroxymethyl)- 8, 3- Pharmablock methylpiperidin- , Inc.) 1-yl)pyrido[4,3-d]pyrimidin-7-
-201 -Ex. Salt Method Structure Name Reagent Form Change yl)naphthalen-2-ol OH
67 5-Ethyl-6-fluoro- 2,2,2- Step 1:
ae:
4-(8-fluoro-2- trifluo [(3R)-3-F (42R,7aS)-2-roacet methylpiperi fluorotetrahydro- ate din-3-1H-pyrrolizin- yl]methanol 7a(511)- hydrochlorid OH yl)methoxy)-4- e (CAS#:
((R)-3- 1956437-13-(hydroxymethyl)- 0, 3- Pharmablock methylpiperidin- , Inc.) 1-yl)pyrido[4,3 -d] pyrimidin-7-yl)naphthalen-2-ol 68 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-C-ANH2 fluoro-3- trifluo methyl-3-F hydroxynaphthal roacet piperidinecar F en-1-y1)-8- ate boxamide N 1\1 N0 fluoro-2- hydrochlorid N (42R,7aS)-2- e (CAS#:
fluorotetrahydro- 1315499-98-OH
1H-pyrrolizin- 9, AA
7a(511)- Blocks) yl)methoxy)pyrid o[4,3-d] pyrimidin-4-y1)-3-methylpiperidine -3-carboxamide
- 202 -Ex. Salt Method Structure Name Reagent Form Change 69 8,01-1 8-(7-(8-Ethy1-3- bis(2, Step 1: 2-hydroxynaphthal 2,2- methyl-8-N
en-1-y1)-8- trifluo azabicyc1o[3.
N N fluoro-2- roacet 2.1loctan-2-N^o"4 (42R,7aS)-2- ate) ol 2,2,2-N
fluorotetrahydro- trifluoroaceta OH 1H-pyrrolizin- te 7a(511)- (Intermediat yl)methoxy)pyrid e M1) o[4,3-d] pyrimidin-4- Step 2: 2-(8-y1)-2-methyl-8- ethy1-3-azabicyclo[3.2.1] (methoxymet octan-2-ol hoxy)naphtha len-l-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (CAS#:

1, LabNetwork) 70 F 60,0H 8-(7-(8-Ethy1-7- bis(2, Step 1: 2-fluoro-3- 2,2- methyl-8-N
hydroxynaphthal trifluo azabicyclo[3.
\
en-1-y1)-8- roacet 2.1loctan-2-N*LOW fluoro-2- ate) ol 2,2,2-(42R,7aS)-2- trifluoroaceta OH
fluorotetrahydro- te 1H-pyrrolizin- (Intermediat 7a(5H)- e M1) yl)methoxy)pyrid o[4,3-d] pyrimidin-4-y1)-2-methy1-8-azabicyclo[3.2.1]
octan-2-ol
- 203 -Ex. Salt Method Structure Name Reagent Form Change 2-(7-(8-Ethy1-7- bis(2, Step 1: 6-fluoro-3- 2,2- methyl-2-F
N io hydroxynaphthal trifluo azabicyc1o[2. , en-1-y1)-8- roacet 2.1]heptan-6-* V6SI fluoro-2- ate) ol 2,2,2-(42R,7aS)-2- trifluoroaceta OH
fluorotetrahydro- te 1H-pyrrolizin- (Intermediat 7a(511)- e M2) yl)methoxy)pyrid o[4,3-d] pyrimidin-4-y1)-6-methy1-2-azabicyclo[2.2.1]
heptan-6-ol 72 (sip 2-(7-(8-Ethy1-7- bis(2, Step 1: 2-fluoro-3- 2,2- azabicyc1o[2.
N
F hydroxynaphthal trifluo 2.1]heptan-6-N =====
I en-1-y1)-8- roacet one fluoro-2- ate) hydrochlorid (42R,7a5)-2-OH
fluorotetrahydro- (Intermediat 1H-pyrrolizin- e N) 7a(511)-yl)methoxy)pyrid o[4,3-d] pyrimidin-4-y1)-2-azabicyclo[2.2.1]
heptan-6-one Additional Step for Example 44 o l<
1\1 N N F
CI
TFA/CH2Cl2 To a stirred solution of tert-butyl ((R)-1-(7-chloro-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-yOpiperidin-3-
- 204 -yl)carbamate (0.27 g, 0.50 mmol, synthesized in an analogous manner to Example 1) in DCM (2.0 mL) was added trifluoroacetic acid (1.50 g, 1.0 mL, 13.42 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at rt for 1 h, and then was concentrated under reduced pressure. The residue was diluted with DCM and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and evaporated to yield the product, which was used directly in the next step. m/z (ESI, +ve ion): 439.0 (M+H)+.
N-OR)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide (Example 73) 0.,NH2 L ) 8 L ) 8 AcCI
DIPEA HCl/Dioxane CH2Cl2 N 0 '= N CH3CN
Step 1 Step 2 OMOM OMOM OH
Example 73 Step 1: N-OR)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(51-1)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidin-3-ypacetamide. To a solution of (R)-1-(7-(8-ethy1-7-fluoro-3-.. (methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yl)piperidin-3-amine (35 mg, 0.06 mmol, prepared according to Example 44) in DCM (0.5 mL) was added DIPEA (21 mg, 0.03 mL, 0.17 mmol, Sigma-Aldrich Corporation), followed by acetyl chloride (5.2 mg, 4.7 1.1.1,õ 0.07 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at rt for 15 min. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford N-((R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)piperidin-3-yOacetamide (25 mg, 0.04 mmol, 67% yield) as yellow solid.
m/z (ESI, +ve ion): 679.2 (M+H)+.
Step 2: N-OR)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-
- 205 -d]pyrimidin-4-yl)piperidin-3-yl)acetamide. N-((R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-ypacetamide (25 mg, 0.04 mmol) was dissolved in acetonitrile (0.5 mL), HC1 (4 M in dioxaneõ 13 mg, 0.01 mL, 0.37 mmol, Sigma-Aldrich Corporation) was added and the reaction mixture was stirred at rt for 0.5 h. The reaction mixture was purified by reverse phase HPLC to afford N-((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-yOacetamide bis(2,2,2-trifluoroacetate) (18 mg, 0.02 mmol, 38 % yield) as yellow solid.
m/z (ESI, +ve ion): 635.2 (M+H)+. 1H NMR (400 MHz, METHANOL-4) 6 ppm 9.25 (d, J=2.7 Hz, 1 H), 7.70 (dd, J9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.09 (dd, J=7.6, 2.6 Hz, 1 H), 5.46 - 5.72 (m, 1 H), 4.81 - 4.91 (m, 1 H), 4.69 - 4.77 (m, 2 H), 4.61 -4.68 (m, 1 H), 4.55 (br d, J=13.0 Hz, 1 H), 3.85 - 4.12 (m, 4 H), 3.67 - 3.76 (m, 1 H), 3.35 -3.53 (m, 2 H), 2.55 -2.85 (m, 2 H), 2.32 -2.53 (m, 4 H), 2.16 -2.28 (m, 2 H), 1.95 -2.13 (m, 4 H), 1.72 - 1.88 (m, 2 H), 0.78 - 0.86 (m, 3 H).
Table 6. Examples 74 to 78 synthesized in an analogous manner to Example 73.
Ex. Salt Structure Name Reagent Form roMe 74 1-((R)-1-(7-(8-ethyl-7- 2,2,2- Step 1: 1-N) F fluoro-3- trifluo isothiocyan N
hydroxynaphthalen-1- roacea ato-2-ilD
4-1:6"*.st N F y1)-8-fluoro-2- th (42R,7aS)-2- te methoxye ane (CAS#:
OH fluorotetrahydro-1H- 38663-85-pyrrolizin-7a(5H)- 3, yl)methoxy)pyrido[4,3- Enamine);
al pyrimidin-4- triethylami yl)piperidin-3-y1)-3-(2- ne methoxyethyl)thiourea
- 206 -Ex. Salt Structure Name Reagent # Form HN-S. N-((R)-1-(7-(8-Ethy1-7- bis(2, Step 1:
0, , 8-0 fluoro-3- 2,2- methanesul N F hydroxynaphthalen-1- trifluo fonyl F, N ==== ..". N y1)-8-fluoro-2- roacea chloride , I
(((2R,7aS)-2- te) (CAS#:
ry F fluorotetrahydro-1H- 124-63-0, OH pyrrolizin-7a(5H)- Sigma-yl)methoxy)pyrido[4,3- Aldrich al pyrimidin-4-y1)-3- Corporatio methylpiperidin-3- n) yOmethanesulfonamide 76 HN-( N-((R)-1-(7-(8-Ethy1-7- bis(2, o fluoro-3- 2,2-N F hydroxynaphthalen-1- trifluo F, N-= ..". N y1)-8-fluoro-2- roacea , I
(((2R,7aS)-2- te) ry F fluorotetrahydro-1H-OH pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-yOacetamide 77 O Methyl ((R)-1-(7-(8- bis(2, Step 1:
HN-µ ethyl-7-fluoro-3- 2,2- methyl 0õ. o hydroxynaphthalen-1- trifluo chloroform N F
F.:, y1)-8-fluoro-2- roacea ate (CAS#:
N ==== .1 N
(((2R,7aS)-2- te) 79-22-1, <-6 0 ,..6,. .... N

fluorotetrahydro-1H- Sigma-OH pyrrolizin-7a(5H)- Aldrich yl)methoxy)pyrido[4,3- Corporatio al pyrimidin-4-y1)-3- n) methylpiperidin-3-yl)carbamate
- 207 -Ex. Salt Structure Name Reagent Form 78 Methyl ((R)-1-(7-(8- 2,2,2- Step 1:
jNH ethyl-7-fluoro-3- trifluo methyl hydroxynaphthalen-1- roacea chloroform y1)-8-fluoro-2- te ate (CAS#:
N
(42R,7aS)-2- 79-22-1, r\C-10)*" fluorotetrahydro-1H- Sigma-pyrrolizin-7a(5H)- Aldrich OH
yl)methoxy)pyrido[4,3- Corporatio al pyrimidin-4- n) yl)piperidin-3-yl)carbamate Table 7. SFC Conditions for Chiral Separation.
Separation SFC Conditions Peaks to Ex. #
Column: Chiralcel OX, 2 x 25 cm 5 Peak 1: Example p.m column 54 Mobile phase: 35% iPrOH with 0.2%
DEA Peak 2: Example Flowrate: 80 mUmin. 55 CI I ---Yield: 160.9 mg was submitted to generate 60.4 mg of peak 1 with an ee of 99% and 53.9 mg of peak 2 with an ee of 95%.
Table 8: Analytical Data of Examples 44 to 78.
MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.16 (s, 1 H), 7.71 (dd, J=9.0, 5.9 Hz, 1 H), 7.35 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (t, J=2.0 Hz, 1 H), 5.47 - 5.72 (m, 1 H), 4.73 - 4.76 (m, 2 H), 44 593.0 4.60 -4.68 (m, 1 H), 4.44 (br dd, J=13.8, 4.6 Hz, 1 H), 3.74 - 4.14 (m, 5 H), 3.63 - 3.73 (m, 1 H), 3.46 - 3.54 (m, 1 H), 2.57 - 2.86 (m, 2 H), 2.28 -2.53 (m, 5 H), 2.16 -2.27 (m, 2 H), 2.04 -2.15 (m, 1 H), 1.85 - 1.99 (m, 2 H), 0.81 (t, J=7.4 Hz, 3 H).
- 208 -MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.19 (s, 1 H), 7.71 (dd, J=9.0, 5.9 Hz, 1 H), 7.35 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.3 Hz, 1 H), 7.07 (d, J=2.5 Hz, 1 H), 5.47 - 5.74 (m, 1 H), 4.73 - 4.76 (m, 2 H), 45 607.0 4.42 (t, J=13.6 Hz, 1 H), 4.22 -4.30 (m, 1 H), 3.85 -4.11 (m, 5 H), 3.46 -3.54 (m, 1 H), 2.56 -2.82 (m, 2 H), 2.33 -2.54 (m, 4 H), 2.14 -2.28 (m, 2 H), 2.01 - 2.14 (m, 4 H), 1.54 (d, J=5.0 Hz, 3 H), 0.81 (t, J=7.4 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.19 (s, 1 H), 7.71 (dd, J=9.2, 5.9 Hz, 1 H), 7.35 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (d, J=2.5 Hz, 1 H), 5.46 - 5.74 (m, 1 H), 4.70 - 4.77 (m, 2 H), 46 607.2 4.40 (t, J=14.2 Hz, 1 H), 4.21 -4.29 (m, 1 H), 3.84 -4.12 (m, 5 H), 3.46 -3.54 (m, 1 H), 2.58 -2.86 (m, 2 H), 2.33 -2.54 (m, 4 H), 2.15 -2.29 (m, 2 H), 2.01 - 2.14 (m, 4 H), 1.54 (d, J=4.8 Hz, 3 H), 0.81 (td, J=7.3, 2.9 Hz, 3 H).
IHNMR (400 MHz, DMSO-d6): 6 ppm 10.77 (br d, J=1.5 Hz, 1 H), 9.28 (d, J=4.2 Hz, 1 H), 7.78 (dd, J=9.1, 6.0 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.03 (s, 1 H), 5.49 -5.65 (m, 1 H), 4.88 - 5.02 (m, 1 H), 4.50 -47 612.3 4.76 (m, 4 H), 4.05 (s, 6 H), 3.76 - 3.97 (m, 4 H), 3.25 - 3.39 (m, 1 H), 2.55 (br d, J=2.3 Hz, 1 H), 1.93 - 2.38 (m, 8 H), 0.74 (t, J=7.3 Hz, 3H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.33 (s, 1 H), 8.05 -8.12 (m, 1 H), 7.91 - 7.99 (m, 1 H), 7.55 - 7.62 (m, 1 H), 7.46 - 7.52 (m, 1 H), 7.34 - 7.43 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.61 - 4.75 (m, 3 48 592.0 H), 4.33 -4.44 (m, 1 H), 3.83 - 4.13 (m, 3 H), 3.58 -3.71 (m, 1 H), 3.41 -3.54 (m, 2 H), 2.11 -2.81 (m, 9 H), 1.76- 1.94 (m, 3 H), 1.32 (s, 3 H), 0.79 - 0.91 (m, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.36 (s, 1 H), 8.09 -8.22 (m, 1 H), 7.87 - 7.97 (m, 1 H), 7.67 - 7.77 (m, 2 H), 7.50 - 7.62 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.65 - 4.76 (m, 3 H), 4.35 - 4.45 (m, 1 49 582.0 H), 3.83 - 4.14 (m, 3 H), 3.62 - 3.71 (m, 1 H), 3.42 -3.57 (m, 2 H), 2.55 -2.83 (m, 2 H), 2.32 - 2.50 (m, 3 H), 2.12 - 2.28 (m, 2 H), 1.76 -1.95 (m, 3 H), 1.28 - 1.37 (m, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.20 - 9.38 (m, 1 H), 8.10 - 8.21 (m, 2 H), 7.66 - 7.76 (m, 2 H), 7.43 - 7.54 (m, 1 H), 5.50 -50 588.0 5.69 (m, 1 H), 4.65 -4.77 (m, 3 H), 4.34 - 4.48 (m, 1 H), 3.82 - 4.11 (m, 3 H), 3.35 -3.75 (m, 4 H), 2.54 - 2.81 (m, 2 H), 2.31 -2.52 (m, 3 H), 2.11 -2.28 (m, 2H), 1.72 - 1.94 (m, 3 H), 1.29 (s, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.22 - 9.31 (m, 1 H), 51 606.2 7.64 -7.76 (m" 1 H) 7.32 - 7.37 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.03 -7.11 (m, 1 H), 5.48 - 5.70 (m, 1 H), 5.01 - 5.16 (m, 1 H), 4.62 -4.75 (m, 2 H), 3.80 - 4.22 (m, 5 H), 3.58 - 3.76 (m, 1 H), 3.44 - 3.56 (m, 1
- 209 -MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
H), 2.31 -2.98 (m, 7 H), 1.98 -2.29 (m, 4 H), 1.80 - 1.93 (m, 1 H), 1.54 - 1.77 (m, 1 H), 0.75 - 0.89 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.10 - 9.35 (m, 1H), 7.82 - 7.96 (m, 1 H), 7.39 (d, J=2.5 Hz, 2 H), 7.22 - 7.29 (m, 1 H), 5.48 - 5.68 (m, 1 H), 4.60 - 4.80 (m, 3 H), 4.27 - 4.48 (m, 1 H), 3.85 -52 604.1 4.15 (m, 3 H), 3.60 - 3.76 (m, 1 H), 3.36 - 3.59 (m, 3 H), 2.66 (s, 2 H), 2.37 (br s, 3 H), 2.10 - 2.27 (m, 2H), 1.85 (br d, J=3.9 Hz, 3 H), 1.31 (d, J=19.5 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.31 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.08 (d, J=2.5 Hz, 1 H), 5.39 - 5.67 (m, 1 H), 4.79 - 4.83 (m, 2 H), 53 608.2 4.57 -4.68 (m, 1 H), 4.29 - 4.43 (m, 1 H), 3.97 - 4.13 (m, 1 H), 3.42 -3.79 (m, 5 H), 2.67 (s, 1 H), 2.50 (br d, J=4.0 Hz, 3 H), 2.10 -2.34 (m, 5 H), 1.72 - 1.94 (m, 3 H), 1.32 (d, J=8.4 Hz, 3 H), 0.76 - 0.90 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.25 (s, 1 H), 7.66 -7.76 (m, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.23 - 7.32 (m, 1 H), 7.02 -7.11 (m, 1 H), 5.49- 5.72(m, 1 H), 4.72 (br d, J=19.5 Hz, 2 54 617.0 H), 4.27 - 4.44 (m, 2 H), 4.13 - 4.25 (m, 1 H), 3.84 -4.13 (m, 4 H), 3.44 -3.57 (m, 1 H), 3.19 - 3.29 (m, 1 H), 2.68 (s, 2 H), 2.28 -2.54 (m, 7 H), 2.11 - 2.26 (m, 3 H), 1.99 - 2.08 (m, 2 H), 0.81 (t, J=7.4 Hz, 3H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.25 (s, 1 H), 7.67 -7.74 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.23 - 7.31 (m, 1 H), 7.06 -7.12 (m, 1 H), 5.47 - 5.70 (m, 1 H), 4.64 - 4.79 (m, 2 H), 4.28 -4.45 55 617.0 (m, 2 H), 4.13 - 4.24 (m, 1 H), 3.85 - 4.13 (m, 4 H), 3.45 - 3.55 (m, 1 H), 3.21 - 3.28 (m, 1 H), 2.68 (s, 2 H), 2.40 (br d, J=6.0 Hz, 7 H), 2.13 - 2.27 (m, 3 H), 2.00 - 2.11 (m, 2 H), 1.79 - 1.94 (m, 1 H), 0.77 -0.86 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.31 (d, J=1.7 Hz, 1 H), 7.79 - 7.89 (m, 1 H), 7.38 - 7.48 (m, 2 H), 7.22 - 7.27 (m, 1 H), 56 614.0 49 - 5 69 (m" 1 H) 4.61 - 4.76 (m, 3 H), 4.33 - 4.44 (m, 1 H), 3.82 -4.12 (m, 3 H), 3.59 - 3.70 (m, 1 H), 3.41 - 3.54 (m, 2 H), 2.54 -2.82 (m, 2 H), 2.31 - 2.50 (m, 3 H), 2.12 - 2.27 (m, 2 H), 1.78- 1.94 (m, 3 H), 1.33 (d, J=7.3 Hz, 3 H).
-210 -MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.32 (d, J=2.1 Hz, 1 H), 7.63 (d, J=8.2 Hz, 1 H), 7.39 - 7.46 (m, 1 H), 7.37 (s, 1 H), 7.18 -7.24 (m 1 H) 6.90 - 6.99 (m, 1 H), 5.44 - 5.70 (m, 1 H), 4.62 - 4.77 57 580.0 "
(m, 3 H), 4.33 - 4.43 (m, 1 H), 3.82 - 4.12 (m, 3 H), 3.60 - 3.72 (m, 1 H), 3.39 -3.57 (m, 2 H), 2.53 -2.84 (m, 2 H), 2.29 -2.51 (m, 3 H), 2.09 -2.27 (m, 2 H), 1.74 - 1.94 (m, 3 H), 1.33 (d, J=3.8 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.31 (d, J=6.3 Hz, 1 H), 7.62 - 7.70 (m, 1 H), 7.35 - 7.43 (m, 1 H), 7.26 - 7.35 (m, 1 H), 7.14 - 7.22 (m, 1 H), 6.99 - 7.08 (m, 1 H), 5.42 - 5.73 (m, 1 H), 4.59 -58 590.0 4.75 (m, 3 H), 4.32 - 4.43 (m, 1 H), 3.82 - 4.13 (m, 3 H), 3.56 - 3.73 (m, 1 H), 3.42 - 3.54 (m, 2 H), 2.49 -2.85 (m, 2 H), 2.09 - 2.49 (m, 7 H), 1.76 - 1.94 (m, 3 H), 1.33 (d, J=9.0 Hz, 3 H), 0.86 - 0.97 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.34 (s, 1 H), 7.59 -7.69 (m, 1 H), 7.37 (s, 2 H), 7.24 - 7.32 (m, 1 H), 5.48 - 5.69 (m, 1 H), 4.64 -4.75 (m, 3 H), 4.35 -4.43 (m, 1 H), 3.82 -4.13 (m, 3 H), 59 598.0 3.62 - 3.71 (m, 1 H), 3.41 -3.56 (m, 2 H), 2.52 - 2.81 (m, 2 H), 2.30 -2.51 (m, 3 H), 2.09 - 2.27 (m, 2 H), 1.75- 1.94 (m, 3 H), 1.33 (d, J=2.3 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.37 (s, 1 H), 7.76 -7.84 (m, 1 H), 7.51 - 7.60 (m, 1 H), 7.42 - 7.50 (m, 1 H), 7.30 - 7.35 (m, 1 H), 7.27 (s, 2 H), 5.49 - 5.73 (m, 1 H), 4.64 - 4.76 (m, 60 562.0 3 H), 4.36 -4.44 (m, 1 H), 3.83 -4.14 (m, 3 H), 3.64 -3.73 (m, 1 H), 3.40 -3.55 (m, 2 H), 2.55 -2.83 (m, 2 H), 2.31 -2.51 (m, 3 H), 2.12 -2.27 (m, 2 H), 1.77 - 1.95 (m, 3 H), 1.33 (s, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.38 (d, J=3.3 Hz, 1 H), 7.66 -7.75 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.23 - 7.31 (m, 1 H), 61 619.0 7.03 -7.11 (m" 1 H) 5.47 - 5.72 (m, 1 H), 4.70 (s, 2 H), 4.47 - 4.64 (m, 2 H), 4.26 - 4.38 (m, 1 H), 3.81 - 4.14 (m, 4 H), 3.68 - 3.78 (m, 1 H), 3.35 - 3.55 (m, 4 H), 2.54 -2.85 (m, 2 H), 2.32 - 2.54 (m, 4 H), 2.11 - 2.27 (m, 2 H), 0.82 (s, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.23 (s, 1 H), 7.66 -7.76 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.24 - 7.31 (m, 1 H), 7.03 -62 620.0 7.13 (m" 1 H) 5.49 - 5.70 (m, 1 H), 4.64 - 4.76 (m, 2 H), 4.29 -4.40 (m, 1 H), 4.16 - 4.27 (m, 2 H), 3.84 - 4.13 (m, 5 H), 3.72 - 3.84 (m, 2 H), 3.43 - 3.54 (m, 1 H), 2.54 - 2.82 (m, 3 H), 2.32 - 2.54 (m, 4 H), 2.09 -2.32 (m, 5 H), 1.72 - 1.84 (m, 1 H), 0.82 (t, J=7.4 Hz, 3 H).
- 211 -MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.16 (d, J=1.7 Hz, 1 H), 7.68 - 7.75 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.22 - 7.31 (m, 1 H), 7.03 -7.11 (m, 1 H), 5.50 - 5.70 (m, 2 H), 4.65 -4.77 (m, 2 H), 63 633.0 4.39 -4.49 (m, 1 H), 3.79 -4.13 (m, 5 H), 3.42 - 3.57 (m, 1 H), 2.56 -2.95 (m, 4 H), 2.42 -2.55 (m, 2 H), 2.31 -2.42 (m, 2 H), 2.15 -2.29 (m, 2 H), 1.88 - 2.14 (m, 3 H), 1.76- 1.88(m, 1 H), 0.77 - 0.87 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.18 - 9.30 (m, 1 H), 7.63 - 7.76 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.22 - 7.30 (m, 1 H), 7.05 -7.11 (m 1 H) 5.45 -5.70 (m, 1 H), 5.12 - 5.27 (m, 1 H), 4.83 -64 "
635.0 4.95 (m, 1 H), 4.64 -4.75 (m, 2 H), 3.81 -4.13 (m, 4 H), 3.43 -3.56 (m, 1 H), 2.55 - 2.88 (m, 3 H), 2.10 - 2.54 (m, 8 H), 1.92 - 2.04 (m, 1 H), 1.66 - 1.78 (m, 1 H), 1.50 - 1.60 (m, 3 H), 0.74 - 0.88 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.37 (d, J=8.5 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 -7.12 (m, 1 H), 5.46 - 5.70 (m, 1 H), 4.62 -4.77 65 622.0 (m, 3 H), 4.44 (br dd, J=20.0, 13.5 Hz, 1 H), 3.81 -4.15 (m, 3 H), 3.35 -3.65 (m, 3 H), 2.56 -2.87 (m, 2 H), 2.29 -2.51 (m, 4 H), 2.13 -2.29 (m, 3 H), 1.75 - 1.93 (m, 3 H), 1.56 - 1.69 (m, 2 H), 0.97 - 1.07 (m, 3 H), 0.83 (br t, J=7.3 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.22 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (dd, J=4.4, 2.7 Hz, 1 H), 5.44 - 5.72 (m, 1 H), 4.61 - 4.77 (m, 3 66 622.2 H), 3.78 - 4.27 (m, 6 H), 3.45 - 3.61 (m, 2 H), 3.35 -3.41 (m, 1H), 2.56 - 2.84 (m, 2 H), 2.33 - 2.51 (m, 4 H), 2.22 (dtd, J=14.4, 7.0, 7.0, 3.1 Hz, 2 H), 1.87 - 2.01 (m, 2 H), 1.69 - 1.81 (m, 1 H), 1.54 - 1.64 (m, 1 H), 0.95 - 1.12 (m, 3 H), 0.78 -0.87 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.23 (s, 1 H), 7.70 (dd, J=9.1, 5.7 Hz, 1 H), 7.25 - 7.35 (m, 2 H), 7.07 - 7.12 (m, 1 H), 5.48 -5.72 (m, 1 H), 4.61 -4.77 (m, 3 H), 4.12 -4.21 (m, 1 H), 3.84 -4.09 67 622.2 (m, 5 H), 3.45 - 3.65 (m, 2 H), 3.35 - 3.40 (m, 1 H), 2.56 - 2.80 (m, 2 H), 2.33 -2.51 (m, 4 H), 2.14 -2.29 (m, 2 H), 1.86 -2.01 (m, 2 H), 1.68 - 1.81 (m, 1 H), 1.55 - 1.64 (m, 1 H), 0.97 - 1.15 (m, 3 H), 0.78 -0.88 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.22 (dd, J=11.7, 2.3 Hz, 1 H), 7.70 (dd, J=8.0, 5.7 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 68 635.2 (t, J=9.6 Hz, 1 H), 7.09 (t, J=2.6 Hz, 1 H), 5.46 -5.76 (m, 1 H), 4.81 -4.90 (m, 1 H), 4.64 -4.73 (m, 2 H), 4.48 -4.61 (m, 1 H), 3.81 -4.15 (m, 3 H), 3.46 - 3.65 (m, 3 H), 2.55 - 2.84 (m, 2 H), 2.16 - 2.51 (m, 7 H), 1.79 - 1.97 (m, 3 H), 1.28 (s, 3 H), 0.77 - 0.89 (m, 3 H).
-212 -MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4): 6 ppm 8.86 - 9.23 (m, 1 H), 7.66 (d, J=7.3 Hz, 1 H), 7.36 - 7.44 (m, 1 H), 7.32 (s, 1 H), 7.16 -69 616.3 7.23 (m, 1 H), 6.98 - 7.10 (m, 1 H), 5.45 - 5.70 (m, 1 H), 5.06 -5.23 (m, 1 H), 4.57 - 4.77 (m, 4 H), 3.79 - 4.19 (m, 3 H), 3.44 - 3.57 (m, 1 H), 1.62 - 3.21 (m, 16 H), 1.35 (s, 2 H), 0.84- 1.00 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4): 6 ppm 8.91 - 9.22 (m, 1 H), 7.71 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.1 Hz, 1 H), 7.28 (t, J=9.4 70 634.3 Hz, 1 H), 7.02 -7.14 (m, 1 H), 5.48 - 5.70 (m, 1 H), 4.79 -5.24 (m, 2 H), 4.60 -4.77 (m, 3 H), 3.82 - 4.21 (m, 3 H), 3.46 - 3.57 (m, 1 H), 1.65 -2.81 (m, 16 H), 1.26- 1.36 (m, 2 H), 0.76 - 0.90 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4): 6 ppm 9.31 - 9.58 (m, 1 H), 7.70 (dd, J=9.1, 5.7 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.03 - 7.12 (m, 1 H), 5.49 - 5.69 (m, 1 H), 5.34 (br d, J=1.9 71 620.3 Hz, 1 H), 4.68 - 4.78 (m, 4 H), 3.87 - 4.30 (m, 4 H), 3.44 - 3.54 (m, 1 H), 2.55 - 2.93 (m, 3 H), 2.32 - 2.49 (m, 3 H), 2.12 - 2.29 (m, 2 H), 1.79 - 2.07 (m, 3 H), 1.45 - 1.71 (m, 4 H), 0.77 - 0.91 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4): 6 ppm 9.46 - 9.56 (m, 1 H), 9.24 - 9.51 (m, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.01 - 7.14 (m, 1 H), 5.49 -5.75 (m, 1 72 604.3 H), 5.18 (br s, 1 H), 4.84 (br d, J=15.3 Hz, 1 H), 4.39 - 4.77 (m, 2 H), 3.76 -4.13 (m, 4 H), 3.41 - 3.53 (m, 1 H), 3.23 (br s, 1 H), 2.10 -2.77 (m, 11 H), 0.70- 0.90(m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.29 (d, J=15.5 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.3 Hz, 1 H), 7.05 -7.10 (m, 1 H), 5.48 - 5.75 (m, 1 H), 4.90 -4.99 74 710.2 (m, 1 H), 4.62 - 4.75 (m, 2 H), 4.39 -4.61 (m, 2 H), 3.60 - 4.14 (m, 7 H), 3.46 - 3.55 (m, 3 H), 3.35 -3.40 (m, 3 H), 2.31 -2.88 (m, 6 H), 2.12 - 2.29 (m, 3 H), 1.99 - 2.10 (m, 1 H), 1.75- 1.91 (m, 2 H), 0.78 -0.90 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.15 (d, J=6.2 Hz, 1 H), 7.67 - 7.73 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.07 (t, J=2.4 Hz, 1 H), 5.45 - 5.74 (m, 1 H), 4.92 (br d, J=13.2 75 685.2 Hz, 1 H), 4.68 -4.77 (m, 2 H), 4.34 -4.57 (m, 1 H), 3.61 -4.13 (m, 5 H), 3.45 - 3.54 (m, 1 H), 2.98 (d, J=15.5 Hz, 3 H), 2.31 - 2.84 (m, 6 H), 1.98 -2.30 (m, 4 H), 1.79 - 1.92 (m, 2 H), 1.53 (s, 3 H), 0.78 -0.89 (m, 3 H).
-213 -MS
Ex. # m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.16 (d, J=2.5 Hz, 1 H), 7.70 (dd, J=8.4, 6.1 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.3 Hz, 1 H), 7.06 -7.14 (m, 1 H), 5.48 - 5.71 (m, 1 H), 4.94 - 5.19 76 649.2 (m, 1 H), 4.65 - 4.75 (m, 2 H), 4.39 (br dd, J=13.2, 4.8 Hz, 1 H), 3.76 -4.14 (m, 5 H), 3.45 - 3.55 (m, 1 H), 2.59 -2.82 (m, 2 H), 2.33 -2.53 (m, 4 H), 2.06 -2.28 (m, 4 H), 1.75 - 1.96 (m, 5 H), 1.46 (d, J=12.1 Hz, 3 H), 0.77 - 0.89 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.17 (d, J=5.0 Hz, 1 H), 7.68 - 7.73 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.08 (dd, J=5.6, 2.5 Hz, 1 H), 5.50 - 5.71 (m, 1 H), 4.89 - 5.07 (m, 77 665.0 1 H), 4.62 - 4.76 (m, 2 H), 4.47 (br d, J=12.8 Hz, 1 H), 3.79 - 4.13 (m, 4 H), 3.68 - 3.76 (m, 1 H), 3.41 - 3.54 (m, 4 H), 2.55 - 2.86 (m, 2 H), 2.34 -2.53 (m, 4 H), 2.18 -2.32 (m, 2 H), 2.05 -2.15 (m, 2 H), 1.76 - 1.87 (m, 2 H), 1.40 (d, J=12.8 Hz, 3 H), 0.78 -0.91 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.23 (d, J=2.9 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (dd, J=9.6, 2.7 Hz, 1 H), 5.45 -5.73 (m, 1 H), 78 651.2 4.97 (br d, J=10.5 Hz, 1 H), 4.62 - 4.77 (m, 2 H), 4.48 - 4.58 (m, 1 H), 3.80 - 4.15 (m, 4 H), 3.62 - 3.75 (m, 4 H), 3.46 - 3.59 (m, 1 H), 3.34 - 3.42 (m, 1 H), 2.33 - 2.88 (m, 6 H), 2.16 - 2.29 (m, 2 H), 2.08 -2.16 (m, 1 H), 1.98 - 2.07 (m, 1 H), 1.69 - 1.84 (m, 2 H), 0.82 (dt, J=11.6, 7.4 Hz, 3 H).
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide (Example 79) s, - 11 0õ0 0)s:re 0%10 N HCI
OH

* i N N.11 N
0.00.65 HCl/cD) Si DMA IP F N Me0H F

.==== Step 1 Step 2 Example 79 Step 1: 1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(511)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide. An 8-mL vial was charged with 7-(8-ethy1-7-fluoro-3 -(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-
-214 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-ol (40 mg, 0.072 mmol), N,N-diisopropylethylamine (46 mg, 0.06 mL, 0.36 mmol) and N,N-dimethylacetamide (0.4 mL). The solution was stirred at rt for 10 min before HATU (0.11 g, 0.29 mmol) was added. After 10 min, a solution of N-methylpiperidine-3-sulfonamide (13 .. mg, 0.072 mmol, Enamine) in DMA was added to the vial and the reaction was stirred at rt for 30 min. The mixture was purified by column chromatography on silica gel, eluting with 0-50% 3:1 Et0AciEt0H blend in heptane with 2% triethylamine additive to yield 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-N-methylpiperidine-sulfonamide (47 mg, 0.066 mmol, 91 % yield). m/z (ESI): 715.2 (M+H)+.
Step 2: 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide. 1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide (47 mg, 0.066 mmol) was stirred in methanol (0.3 mL) and hydrogen chloride (4.0 M in dioxane, 0.3 mL, 1.32 mmol) at rt for 1 h. Volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d]
pyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide as its TFA salt (16 mg, 0.020 mmol, 30 %
yield). m/z (ESI): 671.0 (M+H)+. 1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.19 (s, 1 H), 7.66 -7.75 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.05 -7.11 (m, 1 H), 5.50 -5.70 (m, 1 H), 4.85 - 4.99 (m, 1 H), 4.78 - 4.83 (m, 1 H), 4.68 - 4.74 (m, 1 H), 4.44 -4.60 (m, 1 H), 3.74 - 4.13 (m, 5 H), 3.55 - 3.65 (m, 1 H), 3.46 - 3.55 (m, 1 H), 2.80 (s, 3 H), 2.56 - 2.78 (m, 2 H), 2.31 -2.53 (m, 5 H), 2.02 -2.29 (m, 4 H), 1.76 - 1.96 (m, 1 H), 0.76 - 0.88 (m, 3 H).
Table 9: Examples 80 to 147 and 176-177. prepared in an analogous manner to Example 79.
Salt Method Ex.# Structure Name Reagent Form Change
-215 -80 5-Ethyl-6-fluoro- Bis(2, Step 1: (R)-2-F 4-(8-fluoro-2-2,2,- methylazepan F (((2R,7aS)-2- trifluo I fluorotetrahydro- roacet hydrochlorid 1H-pyrrolizin- ate) e (CAS#:
7a(511)- 331994-00-4, OH
yl)methoxy)-4- Synnovator) ((R)-2-methylazepan-l-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 81 5-Ethyl-6-fluoro- Bis(2, Step 1: (S)-2-4-(8-fluoro-2- 2,2,- methylazepan F (((2R,7aS)-2- trifluo N
I fluorotetrahydro- roacet hydrochlorid N 1H-pyrrolizin- ate) e (CAS#:
7a(511)- 2431997-40-OH
yl)methoxy)-4- 7, ((S)-2- Synnovator) methylazepan-l-yl)pyrido[4,3 -al pyrimidin-7-so2NH2 yl)naphthalen-2-ol 82 (1-(7-(8-Ethy1-7- 2,2,2-Step 1:
fluoro-3- trifluo (azetidin-3-F
hydroxynaphthale roacet yl)methanesu N ====. N F n-1-y1)-8-fluoro-2- ate lfonamide N*Lok, (42R,7aS)-2- hydrochlorid F N fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 2413904-31-OH
7a(5H)- 9, Enamine) yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)azetidin-3-yl)methanesulfona mide 83 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-Hog-NH2 fluoro-3- trifluo hydroxyazeti hydroxynaphthale roacet dine-3-F n-1-y1)-8-fluoro-2- ate carboxamide (1011. NI 1 (((2R,7aS)-2-trifluoroaceti N fluorotetrahydro- c acid 1H-pyrrolizin- (CAS#:
OH 7a(5H)- 2044797-06-yl)methoxy)pyrido 8, Enamine)
-216 -[4,3-cilpyrimidin-4-y1)-3-hydroxyazetidine-3-carboxamide 84 o%p 5-Ethyl-6-fluoro- 2,2,2-Step 1: 3-C) 4-(8-fluoro-2- trifluo methanesulfo (((2R,7aS)-2- roacet nylpiperidine io N "s. `=== N F fluorotetrahydro- ate (CAS#:
INV)(j1H-pyrrolizin- 290328-56-2, F N 0 '" N
7a(511)- Enamine) yl)methoxy)-4-(3 -OH
(methylsulfonyl)pi peridin-l-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 85 so2NH2 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo piperidine-4-F
hydroxynaphthale roacet sulfonamide n-1-y1)-8-fluoro-2- ate hydrochlorid N====. "*". N
I (((2R,7aS)-2- .. e (CAS#:
N 0 N fluorotetrahydro- 1251923-46-1H-pyrrolizin- 2, Enamine) OH
7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)piperidine-4-csso2NH2 sulfonamide 86 1-(7-(8-Ethyl-7- 2,2,2- Step 1: 3-fluoro-3- trifluo pyrrolidinesu hydroxynaphthale roacet lfonamide n-1-y1)-8-fluoro-2- ate (CAS#:
re'o'"'= (((2R,7aS)-2- 1208507-46-fluorotetrahydro- 3, Enamine) OH 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-cilpyrimidin-4-yl)pyrrolidine-3-sulfonamide
-217 -87 so2NH2 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-<L>
fluoro-3- trifluo azetidinesulf hydroxynaphthale roacet onamide n-l-y1)-8-fluoro-2- ate hydrochlorid (((2R,7aS)-2- e (CAS#:
fluorotetrahydro- 1909318-76-OH 1H-pyrrolizin- 8, Enamine) 7a(5H)-yl)methoxy)pyrido [4,3-cilpyrimidin-4-yl)azetidine-3 -sulfonamide 88 H2Ng 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo azetidine-3-F
hydroxynaphthale roacet carboxamide N ***=. ***41 F n-1-y1)-8-fluoro-2- ate hydrochlorid I N0 (((2R,7aS)-2- e (CAS#:
N fluorotetrahydro- 124668-45-7, 1H-pyrrolizin- Combi-OH
7a(5H)- Blocks Inc.) yl)methoxy)pyrido [4,3-cilpyrimidin-4-ypazetidine-3-carboxamide 89 1-(7-(8-Ethy1-7- 2,2,2- Step 1: N-fluoro-3- trifluo methylpiperi hydroxynaphthale roacet dine-3-N
F n-1-y1)-8-fluoro-2- ate carboxamide "*. N
I N*Leõ,, (((2R,7aS)-2- hydrochlorid F N fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 475060-42-5, OH
7a(5H)- Enamine) yl)methoxy)pyrido [4,3-al pyrimidin-4-y1)-N-methylpipe ridine -3 -carboxamide (S)-1-(7-(8-Ethyl- 2,2,2- Step 1: (S)-7-fluoro-3- trifluo pipe ridine -3 -F hydroxynaphthale roacet carboxylic ( N N F n-1-y1)-8-fluoro-2- ate acid amide 10 I N (((2R,7aS)-2- (CAS#:
F fluorotetrahydro- 88495-55-0, 1H-pyrrolizin- Oakwood OH
7a(5H)- Products, yl)methoxy)pyrido Inc.)
-218 -[4,3-c/Ipyrimidin-4-y1)piperidine-3-carboxamide 91 4-(4-(3-(1H- 2,2,2- Step 1: 1-Imidazo1-1- trifluo (azetidin-3-yl)azetidin-1-y1)- roacet y1)-1H-F 8-fluoro-2- ate imidazole N (((2R,7aS)-2- dihydrochlori fl r& I N e=-=
1.W F uorotetrahydro- de (CAS#:
1H-pyrrolizin-153836-44-3, OH 7a(511)- Enamine) yl)methoxy)pyrido [4,3-c/Ipyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol 92 HO 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-fluoro-3- trifluo methylazetidi hydroxynaphthale roacet 11-3-ol N 1%1 N*(e6"---5 n-l-y1)-8-fluoro-2- ate hydrochlorid (((2R,7aS)-2- e (CAS#:
fluorotetrahydro- 124668-46-8, OH 1H-pyrrolizin- Advanced 7a(511)- ChemBlocks yl)methoxy)pyrido Inc.) [4,3-c/Ipyrimidin-4-y1)-3-methylazetidin-3-ol 93 4-(4-(Azocan-1- Free Step 1:
y1)-8-fluoro-2- base azocane The product (((2R,7aS)-2- (CAS#: was re-fluorotetrahydro- 1121-92-2, purified 1H-pyrrolizin- Sigma- by column 7a(5H)- Aldrich chromatog OH yl)methoxy)pyrido Corporation) raphy on [4,3-c/Ipyrimidin- silica gel, 7-y1)-5-ethyl-6-eluting fluoronaphthalen- with 0%
2-ol to 100%
(2 M NH3 in Me0H/D
CM) in DCM
-219 -94 5-Ethyl-6-fluoro- 2,2,2-Step 1:
4-(8-fluoro-2- trifluo piperidine N
F (((2R,7aS)-2- roacet (CAS#:

(10 ===== N
I u fluorotetrahydro- ate 89-4, 1,11 F N 1H-pyrrolizin- Spectrum 7a(511)- Chemicals &
OH
yl)methoxy)-4- Laboratory (piperidin-1- Products) yl)pyrido[4,3-alpyrimidin-7-yl)naphthalen-2-ol 95 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo azepan-4-one hydroxynaphthale roacet hydrochlorid F n-1-y1)-8-fluoro-2- ate e (CAS#:
I *L (((2R,7aS)-2- 50492-22-3, N N fluorotetrahydro- Tyger Sci.
1H-pyrrolizin- Inc.) OH 7a(511)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)azepan-4-one 96 H000, rac-(3R,55)-1-(7- 2,2,2- Step 1: rac-F (8-Ethyl-7 -fluoro- trifluo (3R,55)-5-3- roacet methylpiperi :*c hydroxynaphthale ate din-3-ol N n-1-y1)-8-fluoro-2-hydrochlorid (((2R,7aS)-2- e (CAS#:
OH
fluorotetrahydro- 955028-53-2, 1H-pyrrolizin- ChemSpace) 7a(5H)-yl)methoxy)pyrido [4,3-dlpyrimidin-4-y1)-5-methylpiperidin-3-ol 97 OH 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-fluoro-3- trifluo azabicyclo[3.
hydroxynaphthale roacet 2.11octan-8-N "==== N
F n-1-y1)-8-fluoro-2- ate ol (CAS#:
s'=
I N*Le (((2R,7aS)-2- 1331847-92-N fluorotetrahydro- 7, Aurum 1H-pyrrolizin- Pharmatech OH
7a(5H)- LLC) yl)methoxy)pyrido [4,3-dlpyrimidin-
- 220 -4-y1)-3-azabicyclo[3.2.110 ctan-8-ol 6H 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 8-fluoro-3- trifluo methyl-3-F
hydroxynaphthale roacet azabicyc1o[3.
N 1=1 F n-1-y1)-8-fluoro-2- ate 2.11octan-8-t. I N*Legõ, (42R,7aS)-2- ol r F N fluorotetrahydro- hydrochlorid 1H-pyrrolizin- e (CAS#:
OH
7a(511)- 1131846-59-yl)methoxy)pyrido 3, Enamine) [4,3-alpyrimidin-4-y1)-8-methy1-3-azabicyclo[3.2.110 ctan-8-ol 99 HOt 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-fluoro-3- trifluo azabicyclo[4.
hydroxynaphthale roacet 1.01heptan-1-F
NI
N*Le6S n-1-y1)-8-fluoro-2- ate ol (4 hydro 2R,7aS)-2-chlorid fluorotetrahydro- e (CAS#:
OH 1H-pyrrolizin- 1394042-85-7a(511)- 3, yl)methoxy)pyrido Pharmablock, [4,3-dlpyrimidin- Inc.) 4-y1)-3-azabicyclo[4.1.0111 eptan-l-ol 100 OH rel-(3R,45)-1-(7- 2,2,2- Step 1: cis-(8-Ethyl-7-fluoro- trifluo 3,4-3- roacet piperidinedio io N =N F hydroxynaphthale ate 1 N*Leik 11-1-y1)-8-fluoro-2- hydrochlorid F (((2R,7aS)-2- e (CAS#:
fluorotetrahydro- 443648-89-3, OH
1H-pyrrolizin- eNovation 7a(5H)- Chemicals yl)methoxy)pyrido LLC) [4,3-alpyrimidin-4-yl)piperidine-3,4-diol
-221 -101 OH rel-(3S,45)-1-(7- 2,2,2- Step 1:
trans-cyH
(8-Ethyl-7-fluoro- trifluo piperidine-3- roacet 3,4-diol N . "=== N F hydroxynaphthale ate hydrochlorid n- 1 -y1)-8-fluoro-2- e (CAS#:
N 0 =
(42R,7aS)-2- 443648-97-3, fluorotetrahydro- eNovation OH
1H-pyrrolizin- Chemicals 7a(5H)- LLC) yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidine-3,4-diol 102 HO,õ0,0H (3R,5R)-1-(7-(8- 2,2,2-Step 1: None Ethyl-7-fluoro-3- trifluo (3R,5R)-F
F hydroxynaphthale roacet piperidine-* n-l-y1)-8-fluoro-2- ate 3,5 -diol NO
N (42R,7aS)-2- (CAS#:
fluorotetrahydro- 1043449-04-OH
1H-pyrrolizin- 2, 7a(5H)- ChemBridge) yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)pipe ridine-3,5 -diol 103 rel-(3aR,7aR)-5- 2,2,2- Step 1: rac-= o (7-(8-Ethyl-7- trifluo (3aR,7aR)-F fluoro-3- roacea octahydro-N "=== F hydroxynaphthale te 1H-n-l-y1)-8-fluoro-2- pyrrolo [3,4-N
(42R,7aS)-2- c]pyridin-3 -OH fluorotetrahydro- one (CAS#:
1H-pyrrolizin- 868551-69-3, 7a(5H)- Enamine) yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)octahydro-3H-pyrrolo [3,4-c] pyridin-3 -one
- 222 -104 0õNH2 4-(4-((S)-3- bis(2, Step 1: (S)-3-Additional Aminopiperidin-1- 2,2- Boc- step N F y1)-8-fluoro-2- trifluo aminopiperid similar to N"==== **==
(((2R,7aS)-2- roacea me (CAS#: Example N..3.1%.04N
fluorotetrahydro- te) 216854-23-8, 44 after OH 1H-pyrrolizin- Aurum Step 1 7a(511)- Pharmatech yl)methoxy)pyrido LLC) [4,3-dlpyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 105 4-(4-(3- 2,2,2- Step 1: 3-F Azabicyclo[3.2.1] trifluo azabicyclo[3, N ***.N F octan-3-y1)-8- roacea 2,11octane *L
N fluoro-2- te hydrochlorid (((2R,7aS)-2- e (CAS#:
fluorotetrahydro- 279-82-3, OH
1H-pyrrolizin- Ryan 7a(5H)- Scientific yl)methoxy)pyrido Inc.) [4,3-dlpyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 106 4-(4-(3-(1H- bis(2, Step 1: 3-Cr\IS Imidazol-4- 2,2- (1H-yl)piperidin-1-y1)- trifluo imidazol-3-F 8-fluoro-2- roacea ium-4-(((2R,7aS)-2- te) yl)piperidin-N
fluorotetrahydro- 1-ium OH 1H-pyrrolizin- dichloride 7a(511)- (CAS#:
yl)methoxy)pyrido 784080-46-2, [4,3-dlpyrimidin- Enamine) 7-y1)-5-ethy1-6-fluoronaphthalen-2-ol
- 223 -oeN 4-(4-(3-(1H- bis(2, Step 1: 3-H Pyrazol-5- 2,2-(1H-pyrazol-F yl)piperidin-1-y1)- trifluo 5-N ==== N
F 8-fluoro-2- roacea yl)piperidine N*L016--S
(((2R,7aS)-2- te) dichloride fluorotetrahydro- (CAS#:
OH 1H-pyrrolizin- 774479-26-4, 7a(511)- Enamine) yl)methoxy)pyrido [4,3-dlpyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 0A.0 5-Ethyl-6-fluoro- Free Step 1: 3-After Step 4-(8-fluoro-2- base (1,3-oxazol-2, (((2R,7aS)-2- 5-fractions fluorotetrahydro- yl)piperidine were (10 N ===== N
I N A 1H-pyrrolizin-dihydrochlori washed 1:61 7a(5H)- de (CAS#: with aq.
yl)methoxy)-4-(3-F
1864062-33- NaHCO3 OH (oxazol-5- 8, Enamine) to free yl)piperidin-1- base the y1)pyrido[4,3-product.
al pyrimidin-7-yOnaphthalen-2-ol rf H 1-(7-(8-Ethy1-7- bis(2, Step 1:
fluoro-3- 2,2- 1,2,3,6-N \I
F hydroxynaphthale trifluo tetrahydropyr I n-1-y1)-8-fluoro-2- roacet idin-3-ol (((2R,7aS)-2- ate) (CAS#:
fluorotetrahydro- 84794-16-1, OH 1H-pyrrolizin- Aurum 7a(5H)- Pharmatech) yl)methoxy)pyrido [4,3-alpyrimidin-4-y1)-1,2,3,6-tetrahydropyridin-3-ol
- 224 -110 N-(1-(7-(8-Ethyl- Free Step 1: N-(3- After Step Cro 7-fluoro-3- base piperidyl)met 2, hydroxynaphthale hanesulfona purificatio N N n-1-y1)-8-fluoro-2- mide (CAS#: n was - (((2R,7aS)-2- 944068-21-7, performed N fluorotetrahydro- AA Blocks) with 0.1%
1H-pyrrolizin- NH4OH
in OH
7a(511)- H20 and yl)methoxy)pyrido MeCN
as 14,3-alpyrimidin- mobile 4-yl)piperidin-3- phase, yl)methanesulfona XBridge mide column (19 x 100n-dm 5 um).
111 5-Ethyl-6-fluoro- 2,2,2- Step 1: Additional OH 4-(8-fluoro-4- trifluo (2S,45)-2- step 42S,45)-4-fluoro- roacet (((tert- analogous N N 2- ate butyldimethy to (hydroxymethyDP lsilyl)oxy)me Example yrrolidin-1-y1)-2- thyl)-4- 27 after OH (((2R,7aS)-2- fluoropyrroli Step 2.
fluorotetrahydro- dine 1H-pyrrolizin- (Intermediat 7a(5H)- e Fl) yl)methoxy)pyrido 14,3-alpyrimidin-7-yl)naphthalen-2-ol 112 F (3R,4R)-1-(7-(8- 2,2,2- Step 1:
(500H
Ethyl-7-fluoro-3- trifluo (3R,4R)-4-F hydroxynaphthale roacet fluoro-N ==== N F n-1-y1)-8-fluoro-2- ate piperidin-3-ol I (((2R,7aS)-2- hydrochlorid N fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 2055390-10-OH
7a(511)- 6, J&W
yl)methoxy)pyrido Pharmalab) 14,3-alpyrimidin-fluoropiperidin-3-ol
- 225 -113 0.4, /OH 5-Ethyl-6-fluoro- 2,2,2-Step 1: (R)- Additional 4-(8-fluoro-2- trifluo 2-(((tert-step \ N
(((2R,7aS)-2- roacet butyldimethy analogous N0...4õ fluorotetrahydro- ate lsilyl)oxy)me to 1H-pyrrolizin-thyl)pyrrolidi Example OH 7a(5H)- ne 27 after yl)methoxy)-4- (Intermediat Step 2.
((R)-2- e F2) (hydroxymethyl)p yrrolidin-l-yl)pyrido[4,3-alpyrimidin-7-yl)naphthalen-2-ol 114 (3S,45)-1-(7-(8- Free Step 1: After Step ao=OH
Ethyl-7-fluoro-3- base (3S,45)-4- 2, hydroxynaphthale fluoropiperidi purificatio N N F n-1-y1)-8-fluoro-2- n-3-ol n was (((2R,7aS)-2-hydrochlorid performed N 0 N fluorotetrahydro- e (CAS#:
with 0.1%
1H-pyrrolizin- 1523530-61-formic OH
7a(5H)- 1, Combi add in yl)methoxy)pyrido Blocks) H20 and [4,3-cilpyrimidin- MeCN as mobile fluoropiperidin-3- phase, ol XSelect (9x 100 mnt, 5 um).
115 F,õ0õ,OH rac-(3S,5R)-1-(7- 2,2,2- Step 1: rac-(8-Ethy1-7-fluoro- trifluo (3S,55)-5-F
io 3- roacea fluoropiperidi I

Ik hydroxynaphthale te n-3-ol r 0"4 F N n-l-y1)-8-fluoro-2-hydrochloriu (((2R,7aS)-2- de (CAS#:
OH
fluorotetrahydro- 1955505-76-1H-pyrrolizin- 6, Enamine) 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-fluoropiperidin-3-ol
- 226 -116 F4sOH rac-(3S,55)-1-(7- 2,2,2- Step 1:
(8-Ethyl-7-fluoro- trifluo rac-(3R,5R)-F 3- roacea 5_ io NZ I N*NL hydroxynaphthale te fluoropiperidi (110 F N n-1-y1)-8-fluoro-2- n-3-ol (42R,7aS)-2- hydrochlorid OH
fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 1955554-58-7a(5H)- 1, Enamine) yl)methoxy)pyrido [4,3-cilpyrimidin-4-y1)-5-fluoropiperidin-3-ol H
(3S,45)-1-(7-(8- 2,2,2- Step 1:
Ethyl-7-fluoro-3- trifluo (3S,45)-F hydroxynaphthale roacea pyrrolidine-N N n-1-y1)-8-fluoro-2- te 3,4-diol 111 I N*L014' (42R,7aS)-2- (CAS#:
F
fluorotetrahydro- 90481-32-6, OH 1H-pyrrolizin- Ambeed Inc) 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)pyrrolidine-3,4-diol F_\0.0,0H 1-(7-(8-Ethyl-7- 2,2,2- Step 1: 5,5-fluoro-3- trifluo difluoropiperi hydroxynaphthale roacea din-3-ol n-1-y1)-8-fluoro-2- te hydrochlorid (42R,7aS)-2- e (CAS#:
fluorotetrahydro- 1803584-46-OH 1H-pyrrolizin- 4, Enamine) 7a(5H)-yl)methoxy)pyrido [4,3-cilpyrimidin-4-y1)-5,5-difluoropiperidin-
- 227 -((5)-1-(7-(8-Ethyl- 2,2,2- Step 1: R25)-s-NH2 7-fluoro-3- trifluo pyrrolidin-2-F
F hydroxynaphthale roacea yllmethanesu N
I
lfonamide 11-1-y1)-8-fluoro-2- te N (42R,7aS)-2- (CAS#:
fluorotetrahydro- 1821827-86-OH
1H-pyrrolizin- 4, Enamine) 7a(511)-yl)methoxy)pyrido [4,3-a1pyrimidin-4-yl)pyrrolidin-2-yl)methanesulfona mide F OH
F 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 5,5-fluoro-3- trifluo difluoroazepa hydroxynaphthale roacea n-4-ol LN) n-1-y1)-8-fluoro-2- te hydrochlorid N ""=41 I I (((2R,7aS)-2- e (CAS#:
N*V"'= N fluorotetrahydro- 2172603-58-1H-pyrrolizin- 4, Enamine) OH 7a(5H)-yl)methoxy)pyrido [4,3-ci1pyrimidin-4-y1)-5,5-difluoroazepan-4-121 3-(7-(8-Ethy1-7- 2,2,2- Step 1: re1-NH2 fluoro-3- trifluo (1S,55)-8-F
hydroxynaphthale roacet azabicyclo 113.
F n-1-y1)-8-fluoro-2- ate 2.11octane-2-N 1\1 I (((2R,7aS)-2- carboxamide N fluorotetrahydro- hydrochlorid 1H-pyrrolizin-OH
7a(5H)- (Intermediat yl)methoxy)pyrido e G3) [4,3-cilpyrimidin-4-y1)-3-azabicyclo[3.2.110 ctane-l-carboxamide
- 228 -N 5-Ethyl-6-fluoro- 2,2,2- Step 1:
4-(8-fluoro-2- trifluo hexahydro-F (42R,7aS)-2- roacet 1H-furo[3,4-F fluorotetrahydro- ate clpyrrole N
1H-pyrrolizin- hydrochlorid 7a(511)- e (CAS#:
OH yl)methoxy)-4- 60889-32-9, ((3aR,6aS)- Aurum) tetrahydro-1H-furo[3,4-clpyrrol-5(311)-yOpyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 123 rac-(1S,55)-8-(7- bis(2, Step 1: rel-ONI-12 (8-Ethyl-7-fluoro- 2,2- (1R,5R)-3-FN 3- trifluo azabicyc1o[3.
F hydroxynaphthale roacet 2.11octane-1-N
n-l-y1)-8-fluoro-2- ate) carboxamide =
(42R,7aS)-2- hydrochlond fluorotetrahydro-OH
1H-pyrrolizin- (Intermediat 7a(5H)- e G2) yl)methoxy)pyrido [4,3-alpyrimidin-azabicyc1o[3.2.110 ctane-2-carboxamide 124 5-Ethyl-6-fluoro- 2,2,2- Step 1: 2-0)4oH 4-(8-fluoro-2- trifluo (piperidin-3-F (((2R,7aS)-2-roacet yl)propan-2-F fluorotetrah dro- ate 110 N N y ol i F N*L0/4õ 1H-pyrrolizin- (CAS#:
7a(5H)- 252723-21-0, OH
yl)methoxy)-4-(3- Chem-(2-hydroxypropan- Bridge) 2-yl)piperidin-1-y1)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol
- 229 -125 Cf..."OH 5-Ethyl-6-fluoro- 2,2,2- Step 1: (35)-F 4-(8-fluoro-2- trifluo piperidin-3 -F (((2R,7aS)-2- roacet ylmethanol (10 N =====. N
diabi I u fluorotetrahydro- ate (CAS#:
F N 1H-pyrrolizin- 144539-77-5, 7a(511)- Combi-OH
yl)methoxy)-4- Blocks Inc.) ((S)-3-(hydroxymethyl)pi peridin-l-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 126 Methyl (R)-1-(7- 2,2,2-Step 1: (R)- Additional (Ao (8-ethyl-7-fluoro- trifluo 3-methyl step after 3- roacet piperidinecar Step 1.
*F hydroxynaphthale ate boxylate Procedure N
"=== N

n-1-y1)-8-fluoro-2- (CAS#: included 1".
(42R,7aS)-2- 164323-85-7, below.
fluorotetrahydro- Combi-OH 1H-pyrrolizin- Blocks Inc.) 7a(511)-yl)methoxy)pyrido [4,3-dlpyrimidin-4-y1)piperidine-3-carboxylate 127 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo azepan-3-one F hydroxynaphthale roacet hydrochlorid (10 N =====. '=== N
I n-1-y1)-8-fluoro-2- ate e (CAS#:
F N (((2R,7aS)-2- 65326-54-7, fluorotetrahydro- Combi-OH
1H-pyrrolizin- Blocks Inc.) 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)azepan-3-one
- 230 -128 CrOH 5-Ethyl-6-fluoro- 2,2,2- Step 1: (R)-F 4-(8-fluoro-2-trifluo 1-N-Boc-3-io N N F (42R,7aS)-2- roacet hydroxymeth I fluorotetrahydro- ate yl-piperidine F N 1H-pyrrolizin- (CAS#:
7a(511)- 140695-85-8, OH
yl)methoxy)-4- AstaTech, ((R)-3- Inc) (hydroxymethyl)pi peridin-l-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 129 0.0H (R)-1-(7-(8-Ethyl- 2,2,2- Step 1: (R)-F 7-fluoro-3- trifluo azepan-3-ol F hydroxynaphthale roacet hydrochlorid ioNI n-1-y1)-8-fluoro-2- ate e (CAS#:
F
fluorotetrahydro- 8, J&W
N (((2R,7aS)-2- 1956435-25-OH
1H-pyrrolizin- Pharmlab) 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)azepan-3-ol 130 0.0oH (S)-1-(7-(8-Ethyl- 2,2,2- Step 1: (S)-F 7-fluoro-3-trifluo azepan-3-ol N N F hydroxynaphthale roacet hydrochlorid 110 '===
I=n-1-y1)-8-fluoro-2- ate e (CAS#:
F N (((2R,7aS)-2- 1956435-25-fluorotetrahydro- 8, J&W
OH
1H-pyrrolizin- Pharmlab) 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)azepan-3-ol
- 231 -131 a NH2 4-(4-((R)-3- 2,2,2- Step 1: (R)-F Aminoazepan-1-trifluo tert-butyl F y1)-8-fluoro-2- roacet azepan-0 NI Nae65 (((2R,7aS)-2- ate ylcarbamate (10 F gõ, N fluorotetrahydro- (CAS#:
1H-pyrrolizin- 1354351-56-OH
7a(511)- 6, Combi-yl)methoxy)pyrido Blocks Inc.) 14,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol 132 N-((R)-1-(7-(8- 2,2,2- Step 1: (R)- Additional O NH F - Ethyl-7-fluoro-3- trifluo tert-butyl step after .
hydroxynaphthale roacet azepan-3- Step 2.
n-1-y1)-8-fluoro-2- ate ylcarbamate Procedure N. N (42R,7aS)-2- (CAS#: included ' N 0- k= fluorotetrahydro- 1354351-56- below.
1H-pyrrolizin- 6, Combi-OH 7a(511)- Blocks Inc.) yl)methoxy)pyrido 14,3-alpyrimidin-4-yl)azepan-3-y1)-2,2-difluoroacetamide N-((R)-1-(7-(8- 2,2,2- Step 1: (R)- Additional aNH Ethyl-7-fluoro-3- trifluo tert-butyl step after hydroxynaphthale roacet azepan-3- Step 2 F n-1-y1)-8-fluoro-2- ate ylcarbamate analogous N N
I (42R,7aS)-2- (CAS#: to N N fluorotetrahydro- 1354351-56- Example 1H-pyrrolizin- 6, Combi- 132 using OH 7a(5H)- Blocks Inc.) acetyl yl)methoxy)pyrido chloride.
14,3-alpyrimidin-4-yl)azepan-3-yl)acetamide
- 232 -134 r\ro 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
fluoro-3- trifluo 1,2,6,7-F ''sles F hydroxynaphthale roacet tetrahydro-0 NI A __LI,,,, n-1-y1)-8-fluoro-2- ate 3H-azepin-3-0 F N (((2R,7aS)-2- one fluorotetrahydro- hydrochlorid OH
1H-pyrrolizin- e 7a(511)- (Intermediat yl)methoxy)pyrido e I) [4,3-alpyrimidin-4-y1)-1,2,6,7-tetrahydro-3H-azepin-3-one 135 Cy..OH 1-(7-(8-Ethy1-7- 2,2,2- Step 1:
F N fluoro-3- trifluo 2,3,6,7-F hydroxynaphthale roacet tetrahydro-0 ) N:LI ,,,, n-1-y1)-8-fluoro-2- ate 1H-azepin-3-* F LI N (((2R,7aS)-2- ol fluorotetrahydro- hydrochlorid OH
1H-pyrrolizin- e 7a(511)- (Intermediat yl)methoxy)pyrido e J) [4,3-cilpyrimidin-tetrahydro-1H-azepin-3-01 136 (-)_oH 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3_ fluoro-3- trifluo methylazepan F N
N F hydroxynaphthale roacet -3-ol n-1-y1)-8-fluoro-2- ate hydrochlorid u N (((2R,7aS)-2- e F
fluorotetrahydro- (Intermediat OH
1H-pyrrolizin- e H1) 7a(5H)-yl)methoxy)pyrido [4,3-cilpyrimidin-4-y1)-3-methylazepan-3-ol Isomer 1
- 233 -137 Cy-OH 1-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-fluoro-3- trifluo methylazepan N N F hydroxynaphthale roacet -3-ol n-1-y1)-8-fluoro-2- ate hydrochlorid reLe6-1-5 (((2R,7aS)-2-fluorotetrahydro- (Intermediat OH
1H-pyrrolizin- e H2) 7a(511)-yl)methoxy)pyrido [4,3-cilpyrimidin-4-y1)-3-methylazepan-3-ol Isomer 2 138 (R) - 1-(7-(8-Ethyl- 2,2,2-Step 1: (R) - Additional 0AoH 7-fluoro-3- trifluo 3-methyl step after hydroxynaphthale roacet piperidinecar Step 1.
F n-1-y1)-8-fluoro-2- ate boxylate Details (42R,7aS)-2- (CAS#: included 1101 N fluorotetrahydro- 164323-85-7, below.
1H-pyrrolizin- Combi-OH 7a(511)- Blocks Inc.) yl)methoxy)pyrido [4,3-cilpyrimidin-4-yl)piperidine-3-carboxylic acid 139 5-Ethyl-6-fluoro- 2,2,2- Step 1:
4-(8-fluoro-2- trifluo 2,3,6,7-F
F (42R,7aS)-2- roacet tetrahydro-.1 NI NA(fluorotetrahydro- ate 1H-azepine * F N 1H-pyrrolizin- hydrochlorid 7a(5H)-OH
yl)methoxy)-4- (Intermediat (2,3,6,7- e K) tetrahydro-1H-azepin-l-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol
- 234 -F_O=NH2 4-(4-((R)-5-Bis(2, Step 1: tert- Additional Amino-3,3- 2,2,- butyl (R)- step after difluoropiperidin- trifluo (5,5- Step 1 NAN 1-y1)-8-fluoro-2- roacet difluoropiperi similar to N*Le'65N (((2R,7aS)-2- ate) din-3- Example fluorotetrahydro- yl)carbamate 44.
OH 1H-pyrrolizin- (CAS#:
7a(5H)- 2089320-98-yl)methoxy)pyrido 7, Advanced [4,3-alpyrimidin- ChemBlocks 7-y1)-5-ethyl-6- Inc.) fluoronaphthalen-2-ol 141 OH 1-(7-(8-Ethyl-7- 2,2,2- Step 1: Additional fluoro-3- trifluo azepan-4-one step after hydroxynaphthale roacea hydrochlorid Step 1.

F n-1-y1)-8-fluoro-2- te e (CAS#: Procedure ""=
,1 (((2R,7aS)-2- 50492-22-3, included Ne"4 N fluorotetrahydro- Tyger Sci. below.
1H-pyrrolizin- Inc.) OH 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-yl)azepan-4-ol rk )I-1 1-(7-(8-Ethy1-7- 2,2,2- Step 1: Additional fluoro-3- trifluo azepan-4-one step after hydroxynaphthale roacea hydrochlorid Step 1.
N ***%. === N F n-1-y1)-8-fluoro-2- te e (CAS#: Procedure I (((2R,7aS)-2- 50492-22-3, included N 0 ' N fluorotetrahydro- Tyger Sci. below.
OH 1H-pyrrolizin- Inc.) 7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-methylazepan-4-ol
- 235 -143 NH2 4-(4-(4- 2,2,2- Step 1:
Additional Aminoazepan-1- trifluo azepan-4-one step after y1)-8-fluoro-2- roacea hydrochlorid Step 1.
) 41 F (42R,7aS)-2- te e (CAS#: Procedure ".
N*L
fluorotetrahydro- 50492-22-3, included 0 1H-pyrrolizin- Tyger Sci. below.
7a(511)- Inc.) OH yl)methoxy)pyrido [4,3-dlpyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 144 5-Ethyl-6-fluoro- 2,2,2- Step 1: Additional 4-(8-fluoro-2- trifluo azepan-4-one step after (42R,7aS)-2- roacea hydrochlorid Step 1.
N ==== N F fluorotetrahydro- te e (CAS#:
Procedure I 1H-pyrrolizin- 50492-22-3, included N
7a(5H)- Tyger Sci. below.
yl)methoxy)-4-(4- Inc.) OH
methyleneazepan-1-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol 145 CN 3-(7-(8-Ethy1-7- 2,2,2- Step 1: 3-F
fluoro-3- trifluo azabicyclo[3.
hydroxynaphthale roacet 2.11octane-6-F n-1-y1)-8-fluoro-2- ate carbonitrile N 1%1 (42R,7aS)-2- hydrochlorid N fluorotetrahydro-1H-pyrrolizin- (Intermediat OH 7a(5H)- e L2) yl)methoxy)pyrido [4,3-dlpyrimidin-azabicyclo[3.2.110 ctane-6-carbonitrile Isomer Mix 1
- 236 -146 C N 3 -(7-(8-Ethy1-7- 2,2,2- Step 1: 3-fluoro-3- trifluo azabicyclo [3.
hydroxynaphthale roacet 2 .11octane-6-F n-l-y1)-8-fluoro-2- ate carbonitrile N fluorotetrahydro-(((2R,7aS)-2- h drochlorid 1H-pyrrolizin- (Intermediat N
OH 7a(511)- e L2) yl)methoxy)pyrido [4,3-d1pyrimidin-4-y1)-3 -azabicyclo [3.2.110 ctane-6-carbonitrile Isomer Mix 2 147 cN 3-(7-(8-Ethyl-7- 2,2,2- Step 1: 8-fluoro-3- trifluo oxa-3 -hydroxynaphthale roacet azabicyclo 113.
F n-1-y1)-8-fluoro-2- ate 2 .11octane-6-(10 N
I õ1 (((2R,7aS)-2- carbonitrile F
N N fluorotetrahydro- hydrochlorid 1H-pyrrolizin-OH 7a(511)- (Intermediat yl)methoxy)pyrido e L1) [4,3-dlpyrimidin-4-y1)-3 -azabicyclo 113.2.2111 onane-6-carbonitrile 176 (R)-1-(7-(8-Ethyl- Free Step 1:
OH
7-fluoro-3- base Intermediate hydroxynaphthale Q1 cS
N n-l-y1)-8-fluoro-2-ON (42R,7aS)-2-fluorotetrahydro-OH 1H-pyrrolizin-7a(5 H)-yl)methoxy)pyrido 114,3 -dlpyrimidin-4-y1)-3 -(methyl-d3)piperidin-3-ol
- 237 -177 \.õ.CD3 (S)-1-(7-(8-Ethyl- Free Step 1:
..-- 7-fluoro-3- base Intermediate Th\I F
E hydroxynaphthale Q2 NV N I n-1-y1)-8-fluoro-2-NSo N (42R,7aS)-2-F fluorotetrahydro-OH 1H-pyrrolizin-7a(5H)-Amethoxy)pyrido [4,3-dlpyrimidin-4-y1)-3-(methyl-d3)piperidin-3-ol Additional step for Example 132 J_ (-- ) NH2 F F .A
C )r.
F N F yOF F N 0 F

N N N N
I ______________________________________ > I
/ .6----s N 0 " DIPEA N 0 "
N N
F F
CH2Cl2 OH OH
To a 10-mL round-bottomed flask was added 4-(44(R)-3-aminoazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol (30 mg, 0.05 mmol) and DIPEA (32 mg, 43 uL, 0.25 mmol, Sigma-Aldrich Corporation) in DCM (0.5 mL). The mixture was cooled to 0 C before difluoroacetic anhydride (13 mg, 13 uL, 0.07 mmol, Oakwood Products, Inc.) was added. The reaction was stirred at rt for 2 h. The reaction mixture was diluted with brine (5 mL) and extracted with Et0Ac (3 x 5mL). The organic layer was concentrated in vacuo.
The material was further purified by reverse phase HPLC to give the desired product as TFA
salt as off-white solid (12 mg, 0.02 mmol, 30% yield).
Additional step for Example 138 o o C)LOH
F N
F N
F NaOH N N
N N I
N 0 " 15 THF/H20 N
N F
F

o o ...- -...- ....- ---
- 238 -To an 8-mL vial was added methyl (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yl)piperidine-3 -carboxylate (10 mg, 0.02 mmol) and 2 N sodium hydroxide (22 uL, 0.04 mmol, Sigma-Aldrich) and THF (74 4). The reaction was stirred at rt overnight. The reaction mixture was diluted with water (5 mL) and extracted with Et0Ac (2 x 10 mL). The organic extract was washed with brine (5 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was used in the next step without purification and determining yield.
m/z (ESI): 666.2 (M+H)+.
Additional step for Example 141 ,40 OH
NaBH4 NN 6-5F -DCE * N -N

140 F N 0 ' 0N...0 0 0 0 To a 10-mL round-bottomed flask was added 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-4-one (30 mg, 0.046 mmol) and sodium borohydride (5.2 mg, 0.14 mmol) in DCE (0.23 mL). A small amount of Me0H was added and the reaction was stirred at rt for 1 h. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0-20% 2 M NH3.Me0H in CH2C12, to provide 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -dlpyrimidin-4-y1)azepan-4-ol as white solid.
m/z (ESI): 652.2 (M+H)+.
Additional step for Example 142:
- 239 -o 5 (NJ
N N F MeMgBr N N
.63 N 0 ' THF N 0 To a 10-mL round-bottomed flask was added 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y0azepan-4-one (25 mg, 0.04 mmol) and THF
(0.8 mL). The mixture was cooled to 0 C before methylmagnesium bromide solution in THF
(39 4, 0.12 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h.
The crude material was quenched with small amount of water and then purified by column chromatography on silica gel, eluting with a gradient of 0 - 20% (2 M NH3.Me0H
in CH2C12) in CH2C12 to provide 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-4-methylazepan-4-ol as white solid, which was used directly in the next step without further manipulation and determing yield. m/z (ESI): 666.2 (M+H)+.
Additional step for Example 143:

NaBH3CN
N N ammonium acetate N
N 0 = N 0 =
Me0H
o o o o To a 10-mL round-bottomed flask was added 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-4-one (20 mg, 0.03 mmol), ammonium acetate (24 mg, 0.31 mmol, Oakwood Products, Inc.) and methanol (0.6 mL). To the mixture was added sodium cyanoborohydride (4 mg, 0.06 mmol, Oakwood Products, Inc.). The reaction was then stirred at rt overnight. The reaction mixture was diluted with brine (5 mL) and extracted with Et0Ac (3 x 5mL). The organic layer was concentrated in vacuo to give 1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-
- 240 -(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-4-amine, which was used directly in the next step, without further purification and determining yield. m/z (ESI): 651.2 (M+H)+.
Additional Step for Example 144 (NJ Br Q
N F 4.00 pc-N

N 0 ' LiHMDS
THF

====,-To a 25-mL round-bottomed flask was added methyltriphenylphosphonium bromide in THF (41 mg, 0.12 mmol, Sigma-Aldrich Corporation) and THF (0.4 mL). LiHMDS
in (1.0 M in THF, 0.1 mL, 0.11 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h. 1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-4-one (25 mg, 0.04 mmol) was added and the reaction was stirred at rt for 3 h. The reaction mixture was diluted with brine (5 mL) and extracted with Et0Ac (2 x 5 mL). The organic extract was concentrated in vacuo. The crude material was purified by column .. chromatography on silica gel column, eluting with a gradient of 0 -100% 3:1 Et0AciEt0H
(with 1% TEA) in heptane to provide 7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-4-(4-methyleneazepan-1-y1)pyrido[4,3-d]pyrimidine, which was used directly in the next step without further purification and determining yield. m/z (ESI): 648.2 (M+H)+.
Table 10: Analytical Data for Examples 80 to 147 and 176-177.
-241 -MS
Ex.# m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, DMSO-d6) 6 ppm 8.39 (br d, J=3.3 Hz, 1 H), 6.89 (br dd, J=8.8, 5.9 Hz, 1 H), 6.39 - 6.59 (m, 2 H), 6.21 - 6.34 (m, 1 H), 4.65 -4.88 (m, 1 H), 4.10 -4.21 (m, 1 H), 3.77 - 3.87 80 606.2 (m, 2 H), 3.43 - 3.63 (m, 1 H), 2.99 - 3.32 (m, 3 H), 2.76 - 2.96 (m, 1 H), 2.63 -2.74 (m, 1 H), 1.75 - 1.99 (m, 2 H), 1.29- 1.73 (m, 8 H), 1.07 - 1.23 (m, 3 H), 0.89 - 1.02 (m, 1 H), 0.45 - 0.83 (m, 5 H), -0.09 - 0.07 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.19 (d, J=3.3 Hz, 1 H), 7.71 (dd, J=9.1, 5.7 Hz, 1 H), 7.25 - 7.35 (m, 2 H), 7.09 (dd, J=15.7, 2.5 Hz, 1 H), 5.44 - 5.72 (m, 1 H), 4.80 - 5.06 (m, 1 H), 81 606.2 4.67 -4.74 (m, 2 H), 4.27 - 4.44 (m, 1 H), 3.84 - 4.12 (m, 3 H), 3.58 - 3.77 (m, 1 H), 3.43 - 3.54 (m, 1 H), 2.56 - 2.86 (m, 2 H), 2.10 -2.54 (m, 8 H), 1.90 -2.08 (m, 3 H), 1.77 (q, J=12.1 Hz, 1 H), 1.31 - 1.59 (m, 5 H), 0.83 (q, J=7.2 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 8.99 (s, 1 H), 7.66 -7.74 (m, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (s, 1 H), 7.06 (d, 643.2 J=2.5 Hz, 1 H), 5.48 - 5.69 (m, 1 H), 4.98 - 5.26 (m, 1 H), 4.62 -4.74 (m, 3 H), 4.28 - 4.54 (m, 1 H), 3.81 - 4.14 (m, 3 H), 3.44 -3.64 (m, 4 H), 3.02 (s, 1 H), 2.52 - 2.80 (m, 2 H), 2.30 - 2.51 (m, 4 H), 2.10 - 2.25 (m, 2 H), 0.80 (s, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.01 (s, 1 H), 7.66 -7.73 (m, 1 H), 7.31 - 7.35 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.03 -6092 7.09 (m, 1 H), 5.48 -5.70 (m, 1 H), 5.11 -5.30 (m, 1 H), 4.79-.
83 4.91 (m, 1 H), 4.79 - 4.94 (m, 2 H), 4.68 (br d, J=3.6 Hz, 2 H), 4.30 -4.50 (m, 1 H), 3.91 (br d, J=15.0 Hz, 3 H), 3.50 (s, 1 H), 2.65 (s, 2 H), 2.30 -2.54 (m, 4 H), 2.19 (br d, J=3.3 Hz, 2 H), 0.81 (t, J=7.3 Hz, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.17 - 9.23 (m, 1 H), 7.66 -7.75 (m, 1 H), 7.34 (s, 1 H), 7.23 - 7.31 (m, 1 H), 7.04 -7.12 (m, 1 H), 5.50 - 5.72 (m, 1 H), 4.85 -5.01 (m, 1 H), 4.81 (s, 1 84 656.2 H), 4.68 -4.74 (m, 1 H), 4.38 -4.59 (m, 1 H), 3.99 -4.12 (m, 1 H), 3.79 -3.98 (m, 4 H), 3.57 - 3.68 (m, 1 H), 3.45 - 3.55 (m, 1 H), 3.06 (d, J=4.0 Hz, 3 H), 2.55 - 2.83 (m, 2 H), 2.31 - 2.54 (m, 5 H), 2.07 -2.30 (m, 4 H), 1.80 - 1.95 (m, 1 H), 0.75 - 0.86 (m, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.16 (s, 1 H), 7.67 -7.75 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.23 - 7.32 (m, 1 H), 7.04 -85 657.6 7.11(m, 1 H), 5.47 - 5.69 (m, 1 H), 4.80 - 4.91 (m, 2 H), 4.65 -4.73 (m, 2 H), 3.83 -4.15 (m, 3 H), 3.57 - 3.72 (m, 2 H), 3.40 -3.55 (m, 2 H), 2.55 - 2.82 (m, 2 H), 2.32 - 2.54 (m, 6 H), 1.97 -2.31 (m, 4 H), 0.82 (s, 3 H).
- 242 -MS
Ex.# m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.30 - 9.41 (m, 1 H), 7.66 -7.74 (m, 1 H), 7.34 (s, 1 H), 7.23 - 7.31 (m, 1 H), 7.03 -7.11 (m, 1 H), 5.47 - 5.71 (m, 1 H), 4.77 - 4.82 (m, 1 H), 4.65 -86 643.6 4.73 (m, 1 H), 4.33 -4.60 (m, 3 H), 4.17 -4.32 (m, 1 H), 3.82 -4.13 (m, 4 H), 3.44 - 3.55 (m, 1 H), 2.31 - 2.82 (m, 8 H), 2.11 -2.28 (m, 2 H), 0.76 - 0.86 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 8.97 - 9.10 (m, 1 H), 7.66 -7.75 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 87 629.6 7.03 - 7.10 (m, 1 H), 5.47 - 5.71 (m, 1 H), 4.92 -5.41 (m, 2 H), 4.74 (br s, 4 H), 4.37 -4.50 (m, 1 H), 3.82 -4.12 (m, 3 H), 3.42 -3.56 (m, 1 H), 2.31 - 2.81 (m, 6 H), 2.09 - 2.26 (m, 2 H), 0.80 (s, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.01 (s, 1 H) 7.67 -7.73 (m, 1 H) 7.31 - 7.36 (m, 1 H) 7.23 - 7.31 (m, 1 H) 7.03 - 7.08 88 592.2 (m, 1 H) 5.51 -5.71 (m, 1 H) 4.88 - 5.21 (m, 2 H) 4.53 - 4.73 (m, 4 H) 3.73 - 4.15 (m, 4 H) 3.43 - 3.57 (m, 1 H) 2.53 - 2.81 (m, 2 H) 2.31 -2.53 (m, 4 H) 2.11 - 2.27 (m, 2 H) 0.81 (s, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.13 (d, J=1.66 Hz, 1 H) 7.70 (dd, J=9.12, 5.81 Hz, 1 H) 7.33 (d, J=2.70 Hz, 1 H) 7.28 89 635.2 (t, J=9.43 Hz, 1 H) 7.07 (d, J=2.49 Hz, 1 H) 5.44 -5.71 (m, 1 H) 4.59 - 4.76 (m, 3 H) 4.42 - 4.55 (m, 1 H) 3.63 - 4.12 (m, 5 H) 3.42 - 3.57 (m, 1 H) 2.76 (s, 6 H) 2.32 -2.52 (m, 4 H) 2.10 - 2.28 (m, 3 H) 1.80 - 2.09 (m, 3 H) 0.78 - 0.85 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.14 (d, J=2.07 Hz, 1 H) 7.67 - 7.76 (m, 1 H) 7.33 (d, J=2.70 Hz, 1 H) 7.23 - 7.30 (m, 90 621.2 1 H) 7.04 - 7.10 (m, 1 H) 5.48 - 5.70 (m, 1 H) 4.58 -4.68 (m, 2 H) 4.42 - 4.53 (m, 1 H) 3.75 -4.13 (m, 5 H) 3.47 - 3.54 (m, 1 H) 2.56 - 2.82 (m, 4 H) 2.35 - 2.51 (m, 4 H) 2.15 - 2.26 (m, 3 H) 1.91 -2.09 (m, 3 H) 0.79 - 0.84 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.29 (s, 1 H) 9.02 (s, 1 H) 8.08 - 8.14 (m, 1H) 7.67 - 7.74 (m, 2 H) 7.34 (d, J=2.51 Hz, 1 H) 7.28 (t, J=9.41 Hz, 1 H) 7.06 (d, J=2.51 Hz, 1 H) 5.70 - 5.80 91 616.2 (m, 1 H) 5.49 - 5.69 (m, 1 H) 5.22 - 5.38 (m, 2 H) 4.94 - 5.14 (m, 2 H) 4.71 -4.80 (m, 2H) 3.83 -4.14 (m, 3 H) 3.44 - 3.55 (m, 1 H) 2.55 -2.82 (m, 2 H) 2.31 -2.54 (m, 4 H) 2.12 -2.27 (m, 2 H) 0.76 - 0.85 (m, 3 H).
1HNMR (400 MHz, DMSO-d6) 6 ppm 10.69 - 10.88 (br s, 1 H) 9.02 (s, 1 H) 7.73 - 7.82 (m, 1 H) 7.29 - 7.40 (m, 2 H) 6.98 - 7.04 92 580.2 (m, 1 H) 5.47 - 5.66 (m, 1 H) 4.53 - 4.87 (m, 4 H) 4.13 - 4.36 (m, 2 H) 3.80 - 3.92 (m, 2 H) 3.26 - 3.37 (m, 1 H) 2.55 (s, 1 H) 2.00 -2.42 (m, 7H) 1.53 (s, 3 H) 0.73 (t, J=7.32 Hz, 3 H).
- 243 -MS
Ex.# m/z (ESI): 111 NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 8.92 - 9.26 (m, 1 93 606.2 H), 7.56 - 7.93 (m, 1 H), 6.98 - 7.48 (m, 3 H), 5.09 -5.61 (m, 1 H), 4.22 - 4.46 (m, 2 H), 4.04 - 4.19 (m, 4 H), 2.91 - 3.28 (m, 4 H), 1.56 -2.59 (m, 18 H), 0.75 -0.88 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 8.86 - 9.35 (m, 1 H), 7.59 -7.96 (m, 1 H), 7.22 - 7.46 (m, 2 H), 6.88 - 7.18 (m, 1 H), 94 578.2 5.26 - 5.85 (m, 1 H), 4.48 - 4.77 (m, 2 H), 3.84 -4.27 (m, 7 H), 3.39 -3.60 (m, 1 H), 2.06 -2.88 (m, 8 H), 1.89 (br s, 6 H), 0.53 -1.10 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.01 -9.34 (m, 1 H), 7.63 - 7.90 (m, 1 H), 7.21 - 7.46 (m, 2 H), 7.08 (d, J=2.7 Hz, 1 H), 95 606.2 5.42 - 5.78 (m, 1 H), 4.61 - 4.73 (m, 2 H), 4.26 -4.53 (m, 4 H), 3.77 - 4.21 (m, 3 H), 3.36 - 3.59 (m, 1 H), 2.93 - 3.11 (m, 2 H), 2.03 -2.88 (m, 12 H), 0.57 - 0.97 (m, 3 H).
1H NMR (METHANOL-4 400 MHz) 6 9.15 (d, 1H, J=1.3 Hz), 7.70 (dd, 1H, J=6.0, 9.1 Hz), 7.34 (d, 1H, J=2.5 Hz), 7.28 (t, 1H, 96 608.3 J=9.3 Hz), 7.07 (d, 1H, J=2.7 Hz), 5.5-5.7 (m, 1H), 3.8-4.0 (m, 4H), 3.5-3.6 (m, 3H), 3.1-3.2 (m, 1H), 2.6-2.7 (m, 2H), 2.3-2.5 (m, 5H), 2.1-2.3 (m, 3H), 2.05 (s, 1H), 1.9-1.9 (m, 1H), 1.9-2.0 (m, 1H), 1.3-1.4 (m, 1H), 1.10 (d, 3H, J=6.7 Hz), 0.8-0.9 (m, 3H).
IHNMR (METHANOL-4 400 MHz) 6 9.23 (s, 1H), 7.70 (dd, 1H, J=5.9, 9.0 Hz), 7.34 (d, 1H, J=2.5 Hz), 7.27 (t, 1H, J=9.4 Hz), 7.08 (d, 1H, J=2.5 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 (m, 2H), 4.5-4.6 97 620.3 (m, 2H), 4.1-4.2 (m, 3H), 3.8-4.1 (m, 3H), 3.4-3.5 (m, 1H), 3.1-3.2 (m, 1H), 2.5-2.8 (m, 2H), 2.3-2.5 (m, 4H), 2.2-2.3 (m, 4H), 1.87 (br dd, 2H, J=3.3, 7.3 Hz), 1.62 (br d, 2H, J=13.0 Hz), 0.8-0.9 (m, 3H).
IHNMR (METHANOL-4 400 MHz) 6 9.22 (s, 1H), 7.70 (dd, 1H, J=5 .7 , 8.9 Hz), 7.34 (d, 1H, J=2.7 Hz), 7.27 (t, 1H, J=9.4 Hz), 98 634.3 7.08 (d, 1H, J=2.5 Hz), 5.5-5.7 (m, 1H), 4.6-4.7 (m, 1H), 4.5-4.6 (m, 2H), 4.2-4.3 (m, 2H), 3.8-4.1 (m, 3H), 3.4-3.6 (m, 2H), 2.7-2.8 (m, 1H), 2.3-2.6 (m, 6H), 2.1-2.3 (m, 2H), 2.01 (br s, 2H), 1.8-1.9 (m, 2H), 1.59 (br d, 2H, J=12.8 Hz), 1.38 (s, 3H), 0.8-0.9 (m, 3H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.24 (d, J=1.5 Hz, 1 H), 7.68 - 7.76 (m, 1 H), 7.36 (d, J=2.5 Hz, 1 H), 7.29 (t, J=9.4 99 606.3 Hz, 1 H), 7.11 (s, 1 H), 5.51 - 5.70 (m, 1 H), 4.33 -4.57 (m, 2H), 3.84 -4.17 (m, 6 H), 3.45 - 3.60 (m, 2 H), 2.33 -2.54 (m, 7 H), 2.15 -2.29 (m, 3 H), 1.07 (dt, J=9.7, 4.7 Hz, 1 H), 0.79 - 0.87 (m, 4 H), 0.66 - 0.73 (m, 1 H)
- 244 -MS
Ex.# m/z (ESI): 1H NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.30 (br d, J=7.3 Hz, 1 H), 7.53 -7.78 (m, 1 H), 7.15 -7.40 (m, 3 H), 6.93 -7.11 100 610.3 (m, 1 H), 5.47 - 5.70 (m, 1 H), 4.34 - 4.44 (m, 2 H), 3.66 -4.12 (m, 9 H), 3.49 (td, J=10.5, 6.0 Hz, 1 H), 2.54 - 2.61 (m, 1 H), 2.32 - 2.45 (m, 3 H), 2.02 - 2.28 (m, 4 H), 1.86 - 2.00 (m, 1 H), 0.72 -0.89 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.28 (d, J=6.3 Hz, 1 H), 7.70 (dd, J=9.2, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (t, J=2.5 Hz, 1 H), 5.50 - 5.68 (m, 1 H), 4.69 101 610.3 (s, 3 H), 4.36 (dd, J=13.5, 2.8 Hz, 1 H), 4.05 -4.21 (m, 2 H), 3.88 -4.03 (m, 3 H), 3.81 - 3.87 (m, 1 H), 3.73 - 3.79 (m, 1 H), 3.45 -3.55 (m, 1 H), 2.56 - 2.83 (m, 2 H), 2.11 -2.54 (m, 7 H), 1.70 -1.82 (m, 1 H), 0.82 (br t, J=7.4 Hz, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.14 - 9.45 (m, 1 H), 7.60 - 7.77 (m, 1 H), 7.23 - 7.43 (m, 2 H), 6.96 - 7.15 (m, 1 H), 102 610.2 5.31 - 5.90 (m, 1 H), 4.67 - 4.74 (m, 1 H), 4.20 - 4.44 (m, 4 H), 3.41 -4.17 (m, 6 H), 1.98 -2.91 (m, 10 H), 0.63 - 0.89 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.23 (s, 1 H), 7.71 (dd, J=9.1, 5.7 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (d, J=2.5 Hz, 1 H), 5.48 - 5.73 (m, 1 H), 4.61 - 4.74 (m, 2 H), 4.43 - 4.50 (m, 1 H), 4.26 -4.34 (m, 1 H), 3.73 - 4.13 103 633.2 (m, 5 H), 3.63 (td, J=8.9, 1.3 Hz, 1 H), 3.46 - 3.54 (m, 1 H), 3.13 -3.23 (m, 1 H), 3.08 (br dd, J=7.4, 2.2 Hz, 1 H), 2.88 - 2.96 (m, 1 H), 2.56 -2.80 (m, 2 H), 2.33 -2.52 (m, 4 H), 2.17 -2.31 (m, 4 H), 0.77 - 0.86 (m, 3 H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.16 (s, 1 H), 7.71 (dd, J=9.2, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (d, J=2.5 Hz, 1 H), 5.44 - 5.72 (m, 1 H), 4.73 - 4.75 104 593.2 (m, 2 H), 4.61 (br d, J=13.4 Hz, 1 H), 4.41 (br dd, J=9.0, 5.6 Hz, 1 H), 3.75 - 4.14 (m, 5 H), 3.63 - 3.72 (m, 1 H), 3.46 - 3.54 (m, 1 H), 2.56 -2.82 (m, 2 H), 2.44 - 2.52 (m, 2 H), 2.17 - 2.42 (m, 5 H), 2.08 - 2.15 (m, 1 H), 1.85 - 1.99 (m, 2 H), 0.81 (td, J=7.4, 1.9 Hz, 3H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.16 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (d, J=2.5 Hz, 1 H), 5.46 - 5.73 (m, 1 H), 4.61 - 4.74 105 604.0 (m, 4 H), 3.83 - 4.17 (m, 3 H), 3.70 (br dd, J=12.3, 6.1 Hz, 2 H), 3.46 - 3.54 (m, 1 H), 2.55 - 2.86 (m, 2 H), 2.33 - 2.52 (m, 6 H), 2.22 (ddd, J=10.7, 7.1, 3.3 Hz, 2H), 1.93 - 1.98 (m, 1 H), 1.72 -1.84 (m, 3 H), 1.61 (br d, J=13.0 Hz, 2 H), 0.82 (td, J=7.4, 2.1 Hz, 3H).
- 245 -MS
Ex.# m/z (ESI): 111 NMR
(M+H)+
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.14 (s, 1 H), 8.90 (dd, J=2.5, 1.3 Hz, 1 H), 7.71 (dd, J=9.2, 5.9 Hz, 1 H), 7.53 (d, J=4.0 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (d, J=2.5 Hz, 1 H), 5.46 - 5.73 (m, 1 H), 4.82 - 4.91 (m, 1 H), 106 644.4 4.66 -4.73 (m, 2H), 3.83 -4.15 (m, 3 H), 3.59- 3.72(m, 2H), 3.35 -3.53 (m, 3 H), 2.54 -2.85 (m, 2 H), 2.32 -2.51 (m, 5 H), 2.14 - 2.27 (m, 2 H), 1.95 - 2.14 (m, 3 H), 0.81 (br t, J=7.3 Hz, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.16 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.61 (dd, J=3.3, 2.3 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.08 (d, J=2.3 Hz, 1 H), 107 644.2 6.31 (dd, J=5.2, 2.1 Hz, 1 H), 5.42 - 5.66 (m, 1 H), 4.81 -4.94 (m, 1 H), 4.63 - 4.71 (m, 2 H), 3.82 - 4.17 (m, 3 H), 3.60 - 3.75 (m, 2 H), 3.45 - 3.54 (m, 1 H), 3.20 - 3.30 (m, 2 H), 2.56 - 2.84 (m, 2 H), 2.19 - 2.48 (m, 7 H), 1.90 - 2.13 (m, 3 H), 0.82 (t, J=7.3 Hz, 3 H).
1HNMR (400 MHz, DMSO-d6) 6 ppm 9.88 (s, 1 H), 9.10 (s, 1 H), 8.27 (d, J=5.9 Hz, 1 H), 7.77 (dd, J=9.1, 6.0 Hz, 1 H), 7.30 - 7.40 (m, 2 H), 6.98 - 7.08 (m, 2 H), 5.15 -5.40 (m, 1 H), 4.53 -4.72 108 645.3 (m, 1 H), 4.32 -4.51 (m, 1 H), 4.07 -4.24 (m, 2 H), 3.46 -3.72 (m, 2 H), 3.29 - 3.39 (m, 1 H), 2.98 -3.15 (m, 3 H), 2.77 -2.92 (m, 1 H), 2.28 - 2.44 (m, 1 H), 2.00 -2.25 (m, 5 H), 1.73 - 1.98 (m, 6 H), 0.75 (br t, J=6.8 Hz, 3 H).
1HNMR (400 MHz, DMSO-d6): 6 ppm 10.56 - 10.86 (m, 1 H), 9.69 - 10.14 (m, 1 H), 9.45 (dd, J=12.3, 2.1 Hz, 1 H), 7.78 (dd, J=9.1, 6.0 Hz, 1 H), 7.32 - 7.40 (m, 2 H), 7.03 (d, J=2.7 Hz, 1 H), 109 592.15 5.87 - 6.07 (m, 2 H), 5.51 - 5.70 (m, 1 H), 4.53 - 4.71 (m, 3 H), 4.43 (br s, 1 H), 4.26 -4.36 (m, 1 H), 4.19 (br dd, J=17.1, 13.0 Hz, 1 H), 3.88 -4.04 (m, 3 H), 3.23 - 3.45 (m, 2 H), 2.52 -2.71 (m, 1 H), 1.98 -2.42 (m, 7 H), 0.74 (t, J=7.3 Hz, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.12 (d, J=2.3 Hz, 1 H), 7.68 (dd, J=9.0, 5.9 Hz, 1 H), 7.32 (d, J=2.7 Hz, 1 H), 7.26 (t, J=9.4 Hz, 1 H), 7.07 (t, J=3.0 Hz, 1 H), 5.22 - 5.48 (m, 1 H), 4.55 110 671.4 - 4.70 (m, 1 H), 4.25 - 4.43 (m, 3 H), 3.48 - 3.89 (m, 3 H), 3.21 -3.29 (m, 2 H), 3.03 (d, J=0.8 Hz, 4 H), 2.13 - 2.55 (m, 6 H), 1.71 -2.08 (m, 6 H), 0.82 (q, J=7.4 Hz, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.41 (s, 1 H), 7.71 (dd, J=9.1, 5.7 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (dd, J=7.3, 2.5 Hz, 1 H), 5.62 - 5.69 (m, 1 H), 5.48 111 612.0 - 5.56 (m, 1 H), 5.06 - 5.15 (m, 1 H), 4.65 -4.71 (m, 1 H), 4.50 -4.56 (m, 1 H), 4.41 - 4.48 (m, 1 H), 4.09 - 4.15 (m, 1 H), 3.92 (br d, J=16.1 Hz, 3 H), 3.75 - 3.88 (m, 1 H), 3.46 - 3.55 (m, 1 H), 2.67 (br d, J=3.3 Hz, 3 H), 2.13 - 2.55 (m, 8 H), 0.81 (t, J=7.1 Hz, 3 H).
- 246 -MS
Ex.# m/z (ESI): 111 NMR
(M+H)+
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.32 (d, J=7.1 Hz, 1 H), 7.70 (dd, J=9.2, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.07 (t, J=2.7 Hz, 1 H), 5.51 -5.67 (m, 1 H), 4.64 112 612.0 - 4.72 (m, 2 H), 4.22 - 4.33 (m, 2 H), 3.86 - 4.19 (m, 6 H), 3.46 -3.56 (m, 1 H), 2.55 - 2.82 (m, 2 H), 2.33 - 2.54 (m, 5 H), 2.15 -2.29 (m, 2 H), 1.99 - 2.10 (m, 1 H), 0.82 (t, J=7.4 Hz, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.35 (d, J=4.2 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 7.07 (dd, J=6.5, 2.7 Hz, 1 H), 5.49 - 5.69 (m, 1 H), 113 594.0 4.85 -4.94 (m, 1 H), 4.71 (s, 2 H), 4.13 - 4.27 (m, 2 H), 3.93 (br d, J=3.3 Hz, 5 H), 3.49 (br dd, J=10.3, 4.9 Hz, 1 H), 2.66 (br s, 2 H), 2.44 - 2.57 (m, 2 H), 2.30 - 2.43 (m, 3 H), 2.07 - 2.27 (m, 5 H), 0.78 - 0.86 (m, 3 H).
IHNMR (500 MHz, DMSO-d6) 6 ppm 9.23 (d, J=5.9 Hz, 1 H), 7.77 (dd, J=9.2, 6.0 Hz, 1 H), 7.32 - 7.37 (m, 2 H), 7.02 (dt, J=3.4, 114 612.2 1.0 Hz, 1 H), 5.32 - 5.72 (m, 1 H), 4.60 -4.77 (m, 1 H), 3.68 -4.10 (m, 4 H), 1.84 -2.41 (m, 7 H), 0.70 -0.76 (m, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.43 (d, J=7.3 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.20 - 7.37 (m, 2 H), 7.08 (t, 115 612.3 J=2.4 Hz, 1 H), 5.47 - 5.74 (m, 1 H), 4.92 - 5.14 (m, 1 H), 4.73 (br dd, J=8.3, 3.2 Hz, 3 H), 4.52 (br s, 1 H), 3.72 - 4.35 (m, 8 H), 3.44 - 3.57 (m, 1 H), 2.59 - 2.91 (m, 2 H), 2.29 - 2.55 (m, 5 H), 2.10 -2.28 (m, 3 H), 0.82 (t, J=7.3 Hz, 3 H).
IHNMR (400 MHz, METHANOL-4) 6 ppm 9.26 (d, J=7.7 Hz, 1 H), 9.12 (s, 1 H), 7.70 (dd, J=9.1, 6.0 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.27 (t, J=9.4 Hz, 1 H), 6.93 - 7.19 (m, 1 H), 5.52 - 5.69 (m, 1 H), 5.49 (s, 1 H), 5.04 - 5.22 (m, 1 H), 4.57 (br t, J=12.4 Hz, 1 116 612.3 H), 4.47 (br dd, J=9.2, 5.2 Hz, 1 H), 4.26 (br dd, J=8.2, 4.0 Hz, 1 H), 4.08 (br dd, J=14.3, 2.6 Hz, 1 H), 3.86 - 4.03 (m, 3 H), 3.45 -3.66 (m, 2 H), 2.73 - 2.81 (m, 1 H), 2.53 - 2.72 (m, 2 H), 2.43 -2.52 (m, 2 H), 2.37 (br dd, J=11.2, 5.7 Hz, 4 H), 2.14 - 2.26 (m, 3 H), 0.81 (br t, J=7.3 Hz, 4H).
IHNMR (400 MHz, METHANOL-d4) 6 ppm 9.36 (d, J=6.7 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.21 - 7.44 (m, 2 H), 7.09 (dd, J=11.3, 2.5 Hz, 1 H), 5.47 - 5.70 (m, 1 H), 4.63 -4.77 (m, 3 H), 117 4.20 (br s, 1 H), 4.13 -4.53 (m, 2 H), 4.12 - 4.60 (m, 1 H), 3.84 -596.3 4.10 (m, 1 H), 3.78 - 4.02 (m, 3 H), 3.42 - 3.55 (m, 1 H), 2.56 -2.82 (m, 2 H), 2.31 -2.53 (m, 4 H), 2.11 -2.26 (m, 2 H), 1.24 (s, 3 H), 0.82 (dt, J=10.6, 7.4 Hz, 3 H).
- 247 -MS
Ex.# m/z (ESI): 11-1 NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.33 - 9.41 (m, 1 H), 7.67 -7.74 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 118 630.0 7.06 -7.12 (m, 1 H), 5.51 - 5.71 (m, 1 H), 4.67 -4.76 (m, 2 H), 4.26 - 4.47 (m, 4 H), 3.83 - 4.11 (m, 4 H), 3.46 - 3.57 (m, 1H), 2.32 -2.82 (m, 7 H), 2.12 -2.31 (m, 3 H), 0.77 - 0.86 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.32 - 9.44 (m, 1 H), 7.65 - 7.75 (m, 1 H), 7.33 - 7.41 (m, 1 H), 7.28 (s, 1 H), 7.00 -119 657.0 7.10 (m, 1 H), 5.50 - 5.71 (m, 1 H), 5.16 - 5.30 (m, 1 H), 4.84-4.92(m, 1 H), 4.12 -4.35 (m, 2H), 3.83 - 4.10 (m, 4H), 3.44 -3.55 (m, 1 H), 3.35 - 3.41 (m, 1 H), 2.10 - 2.89 (m, 13 H), 0.75 -0.87 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.26 - 9.31 (m, 1 H), 7.66 -7.74 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.24 - 7.31 (m, 1 H), 120 644.0 7.05 -7.12 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.62 -4.74 (m, 2 H), 4.22 -4.45 (m, 3 H), 3.83 -4.15 (m, 5 H), 3.45 - 3.56 (m, 1 H), 2.55 -2.93 (m, 3 H), 2.32 - 2.54 (m, 6 H), 2.11 -2.31 (m, 3 H), 0.75 - 0.86 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.18 (s, 1 H), 7.66 -7.73 (m, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.27 (s, 1 H), 7.08 (s, 1 H), 5.46 - 5.72 (m, 1 H), 5.05 - 5.22 (m, 1 H), 4.52 - 4.73 (m, 3 H), 121 647.2 3.72 -4.14 (m, 4 H), 3.45 - 3.66 (m, 2 H), 2.67 (s, 3 H), 2.31 -2.54 (m, 4 H), 2.05 - 2.30 (m, 4 H), 1.95 (s, 3 H), 1.54 - 1.66 (m, 1 H), 0.75 - 0.87 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.33 - 9.40 (m, 1 H), 7.66 -7.74 (m, 1 H), 7.31 - 7.37 (m, 1 H), 7.22 - 7.31 (m, 1 H), 122 642.2 7.03 - 7.11 (m, 1 H), 5.48 - 5.72 (m, 1 H), 4.82 - 4.91 (m, 2 H), 4.63 -4.73 (m, 1 H), 4.26 - 4.49 (m, 1 H), 3.68 - 4.16 (m, 9 H), 3.45 - 3.58 (m, 1 H), 2.54 - 2.82 (m, 4 H), 2.30 - 2.54 (m, 4 H), 2.13 -2.27 (m, 2 H), 0.70 - 0.93 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.23 (s, 1 H), 7.66 -7.74 (m, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.23 - 7.31 (m, 1 H), 7.06 -123 647.2 7.10(m, 1 H), 5.45 - 5.71 (m, 2 H), 5.21 - 5.32 (m, 1 H),4.73 (br s, 2 H), 3.82 - 4.15 (m, 3 H), 3.44 - 3.56 (m, 1 H), 2.94 - 3.04 (m, 1 H), 2.53 -2.82 (m, 2 H), 2.34 - 2.53 (m, 4 H), 1.91 - 2.25 (m, 10 H), 0.83 (s, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.04 - 9.37 (m, 1 H), 7.61 - 7.79 (m, 1 H), 7.22 - 7.43 (m, 2 H), 6.88 - 7.17 (m, 1 H), 5.27 - 5.79 (m, 1 H), 4.96 - 5.15 (m, 1 H), 4.54 - 4.80 (m, 2 H), 124 636.4 3.79 -4.16 (m, 3 H), 3.25 - 3.65 (m, 3 H), 3.00 - 3.26 (m, 1 H), 1.46 -2.82 (m, 13 H), 1.26 (s, 3 H), 1.31 (s, 3 H), 0.71 - 0.97 (m, 3 H).
- 248 -MS
Ex.# m/z (ESI): 11-1 NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.18 (s, 1 H), 7.65 -7.88 (m, 1 H), 7.34 (d, J=2.5 Hz, 2 H), 6.94 - 7.14 (m, 1 H), 5.07 -125 608.2 5.88 (m, 1 H), 4.53 -4.74 (m, 4 H), 3.76 -4.17 (m, 3 H), 3.35 -3.68 (m, 5 H), 1.76 - 2.83 (m, 12 H), 1.35 - 1.59 (m, 1 H), 0.78 -0.83 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.02 - 9.24 (m, 1 H), 126 636.2 7.66 -7.91 (m, 1 H), 6.96 - 7.38 (m, 3 H), 5.46 - 5.72 (m, 1 H), 4.48 -4.75 (m, 3 H), 3.83 -4.41 (m, 6 H), 3.71 (m, 3 H), 3.40 -3.58 (m, 1 H), 1.70 - 3.03 (m, 13 H), 0.80 - 0.85 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.06 - 9.71 (m, 1 H), 7.57 - 7.83 (m, 1 H), 7.22 - 7.37 (m, 2 H), 6.87 - 7.11 (m, 1 H), 127 606.2 5.30 - 6.03 (m, 1 H), 4.55 - 4.75 (m, 4 H), 4.24 - 4.46 (m, 2 H), 3.75 - 4.11 (m, 3 H), 3.43 - 3.58 (m, 1 H), 2.31 - 2.80 (m, 8 H), 2.10 - 2.27 (m, 4 H), 1.89 - 2.05 (m, 2 H), 0.72 - 0.93 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.14 - 9.43 (m, 1 H), 7.61 -7.92 (m, 1 H), 7.20 - 7.39 (m, 2 H), 7.00 - 7.18 (m, 1 H), 128 608.2 5.36 -5.85 (m, 1 H), 4.56 -4.83 (m, 4 H), 3.78 -4.17 (m, 3 H), 3.36 - 3.71 (m, 5 H), 1.73 -2.82 (m, 12 H), 1.39- 1.63 (m, 1 H), 0.74 - 0.92 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.26 - 9.47 (m, 1 H), 7.52 - 7.94 (m, 1 H), 7.18 - 7.37 (m, 2 H), 6.91 -7.11 (m, 1 H), 5.47 -5.79 (m, 1 H), 4.64 -4.74 (m, 2 H), 4.34 -4.51 (m, 1 H), 129 608.2 3.74 - 4.22 (m, 7 H), 3.41 - 3.58 (m, 1 H), 2.56 - 2.91 (m, 2 H), 2.27 -2.54 (m, 4 H), 1.90 - 2.27 (m, 6 H), 1.39 - 1.83 (m, 2 H) 1.44- 1.79 (m, 2 H), 0.51 -0.99 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.28 - 9.59 (m, 1 H), 7.62 -7.99 (m, 1 H), 7.20 - 7.49 (m, 2 H), 7.03 - 7.13 (m, 1 H), 130 608.2 5.21 - 6.01 (m, 1 H), 4.65 - 4.77 (m, 2 H), 4.35 - 4.50 (m, 1 H), 3.74 - 4.29 (m, 7 H), 3.43 -3.56 (m, 1 H), 2.29 - 2.81 (m, 6 H), 1.88 -2.26 (m, 6 H), 1.41 - 1.84 (m, 2 H), 0.73 -0.94 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.12 - 9.41 (m, 1 H), 7.71 (dd, J=9.1, 6.0 Hz, 1 H), 7.16 - 7.45 (m, 2 H), 6.90 -7.12 131 607.2 (m, 1 H), 5.37 - 6.01 (m, 1 H), 4.67 -4.77 (m, 2 H), 3.78 -4.48 (m, 8 H), 3.42 - 3.66 (m, 1 H), 1.95 - 2.87 (m, 12 H), 1.51- 1.90 (m, 2 H), 0.79 -0.85 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.03 - 9.54 (m, 1 H), 7.57 -7.80 (m, 1 H), 7.21 - 7.40 (m, 2 H), 6.95 - 7.14 (m, 1 H), 5.87 - 6.38 (m, 1 H), 5.40 - 5.71 (m, 1 H), 4.90 - 5.03 (m, 1 H), 132 685.2 4.51 -4.65 (m, 3 H), 4.01 -4.37 (m, 3 H), 3.83 - 3.99 (m, 2 H), 3.61 -3.78 (m, 1 H), 3.43 -3.56 (m, 1 H), 1.90 - 2.89 (m, 12 H), 1.34 - 1.78 (m, 2 H), 0.66 - 0.94 (m, 3 H).
- 249 -MS
Ex.# m/z (ESI): 11-1 NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.13 - 9.54 (m, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.24 - 7.44 (m, 2 H), 7.04 -7.15 133 649.4 (m, 1 H), 5.16 - 5.90 (m, 1 H), 4.89 -4.93 (m, 1 H), 4.23 -4.67 (m, 4 H), 3.80 - 4.20 (m, 4 H), 3.38 - 3.68 (m, 2 H), 2.01 (s, 15 H), 1.26 - 1.76 (m, 2 H), 0.66 - 0.92 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.06 - 9.36 (m, 1 H), 7.66 -7.77 (m, 1 H), 7.19 -7.49 (m, 2 H), 6.98 -7.12 (m, 1 H), 134 604.2 6.81 -6.93 (m, 1 H), 5.85 -6.33 (m, 1 H), 5.51 -5.76 (m, 1 H), 4.55 -4.73 (m, 4 H), 4.28 -4.50 (m, 2 H), 3.80 - 4.11 (m, 3 H), 3.46 - 3.55 (m, 1 H), 2.91 - 3.06 (m, 2 H), 2.55 - 2.80 (m, 2 H), 2.33 - 2.50 (m, 4 H), 2.14 - 2.28 (m, 2 H), 0.67 - 0.93 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.32 - 9.60 (m, 1 H), 7.64 -7.94 (m, 1 H), 7.34 (m, 2 H), 6.89 -7.14 (m, 1 H), 5.76 -6.26 (m, 2 H), 5.32 - 5.69 (m, 1 H), 4.62 - 4.78 (m, 3 H), 4.49 -135 606.2 4.62(m, 1 H), 3.81 - 4.46 (m, 7 H), 3.42 - 3.54 (m, 1 H), 2.55 -2.89 (m, 3 H), 2.30 - 2.54 (m, 4 H), 1.86 - 2.25 (m, 3 H), 0.71 -0.93 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.45 - 9.71 (m, 1 H), 7.65 -7.84 (m, 1 H), 7.18 - 7.39 (m, 2 H), 6.94 - 7.15 (m, 1 H), 136 622.2 5.46 - 5.96 (m, 1 H), 4.32 - 4.72 (m, 4 H), 3.80 - 4.11 (m, 5 H), 3.38 -3.59 (m, 1 H), 2.32 - 2.87 (m, 6 H), 2.10 - 2.27 (m, 3 H), 1.62 -2.10 (m, 5 H), 1.40 (s, 3 H), 0.67 - 0.83 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.38 - 9.84 (m, 1 H), 7.62 -7.77 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 137 622.2 7.04 - 7.12 (m, 1 H), 5.51 - 5.78 (m, 1 H), 4.62 - 4.78 (m, 2 H), 4.26 -4.62 (m, 2 H), 3.72 -4.14 (m, 5 H), 3.42 - 3.57 (m, 1 H), 2.55 - 2.93 (m, 2 H), 2.29 - 2.53 (m, 4 H), 2.07 - 2.29 (m, 3 H), 1.66 -2.07 (m, 5 H), 1.40 (s, 3 H), 0.57 - 1.00 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.14 - 9.38 (m, 1 H), 138 622.2 7.65 - 7.75 (m, 1 H), 7.24 - 7.41 (m, 2 H), 7.04 - 7.17 (m, 1 H), 5.50 -5.90 (m, 1 H), 4.46 -4.73 (m, 3 H), 3.79 -4.36 (m, 6 H), 3.42 -3.61 (m, 1 H), 1.77 - 3.02 (m, 13 H), 0.80 -0.85 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.23 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.17 - 7.49 (m, 2 H), 6.81 - 7.14 (m, 1 H), 139 590.2 5.80 (s, 2 H), 5.46 -5.71 (m, 1 H), 4.51 -4.76 (m, 3 H), 4.25 -4.35 (m, 3 H), 3.76 - 4.16 (m, 3 H), 3.41 - 3.60 (m, 1 H), 2.09 - 2.85 (m, 12H), 1.36- 1.75(m, 1 H), 0.68 - 1.08 (m, 3 H).
- 250 -MS
Ex.# m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.24 (s, 1 H), 7.71 (dd, J=9.1, 6.0 Hz, 1 H), 7.26 - 7.36 (m, 2 H), 7.08 (dd, J=6.8, 2.6 Hz, 1 H), 5.51 -5.77 (m, 1 H), 4.80 -4.86 (m, 2 H), 4.55 -4.69 140 629.0 (m, 2 H), 4.14 -4.31 (m, 1 H), 3.87 -4.08 (m, 5 H), 3.43 - 3.60 (m, 1 H), 2.72 - 2.85 (m, 1 H), 2.56 - 2.72 (m, 2 H), 2.33 - 2.54 (m, 5 H), 2.12 - 2.31 (m, 2 H), 0.80 (t, J=7.1 Hz, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 8.88 - 9.27 (m, 1 H), 7.59 - 7.80 (m, 1 H), 7.20 - 7.37 (m, 2 H), 6.93 - 7.14 (m, 1 H), 141 608.2 5.13 -5.47 (m, 1 H), 4.32 -4.51 (m, 2 H), 3.86 -4.30 (m, 5 H), 3.36 - 3.56 (m, 3 H), 3.07 - 3.17 (m, 1H), 1.72 - 2.58 (m, 16H), 0.82 (s, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.14 - 9.28 (m, 1 H), 7.56 - 8.03 (m, 1 H), 7.20 - 7.44 (m, 2 H), 6.85 - 7.18 (m, 1 H), 142 622.2 5.35 - 5.95 (m, 1 H), 4.62 - 4.76 (m, 2 H), 3.77 - 4.33 (m, 7 H), 3.46 - 3.61 (m, 1H), 1.81 - 2.89 (m, 13H), 1.47- 1.72(m, 1H), 1.31 (d, J=4.2 Hz, 3 H), 0.69 - 0.97 (m, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 8.97 - 9.35 (m, 1 H), 7.59 -7.90 (m, 1 H), 7.20 - 7.47 (m, 2 H), 6.89 - 7.18 (m, 1 H), 143 607.2 5.40 - 5.78 (m, 1 H), 4.65 - 4.78 (m, 3 H), 4.29 - 4.56 (m, 2 H), 3.74 - 4.17 (m, 5 H), 3.40 - 3.69 (m, 2 H), 2.03 - 2.91 (m, 13 H), 1.66 - 1.83 (m, 1 H), 0.60 - 0.93 (m, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.13 - 9.30 (m, 1 H), 7.64 -7.79 (m, 1 H), 7.22 - 7.46 (m, 2 H), 6.86 - 7.13 (m, 1 H), 144 604.2 5.32 - 5.90 (m, 1 H), 4.83 - 5.01 (m, 2 H), 4.60 - 4.76 (m, 2 H), 4.20 - 4.40 (m, 4 H), 3.80 - 4.11 (m, 3 H), 3.43 - 3.60 (m, 1H), 1.95 -2.91 (m, 14 H), 0.63 -0.93 (m, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.15 (s, 1 H), 7.70 (dd, J=9.1, 6.0 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 145 629.2 Hz, 1 H), 7.06 (t, J=2.5 Hz, 1 H), 5.47 - 5.73 (m, 1 H), 4.82 - 4.98 (m, 1 H), 4.52 -4.75 (m, 3 H), 3.58 -4.15 (m, 5 H), 3.45 - 3.55 (m, 1 H), 3.01 - 3.12 (m, 1 H), 2.54 -2.87 (m, 4 H), 2.30 -2.54 (m, 4 H), 1.99 - 2.29 (m, 6 H), 0.73 - 0.88 (m, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.13 - 9.25 (m, 1 H), 7.69 (br d, J=3.6 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.26 (s, 1 H), 146 629.0 7.03 - 7.14 (m, 1 H), 5.48 - 5.70 (m, 1 H), 4.82 - 5.14 (m, 3 H), 4.61 -4.73 (m, 1 H), 3.83 -4.13 (m, 4 H), 3.45 - 3.73 (m, 2 H), 3.10 - 3.23 (m, 1 H), 2.53 - 2.81 (m, 4 H), 2.31 - 2.53 (m, 5 H), 2.07 -2.26 (m, 3 H), 1.84 - 1.99 (m, 2 H), 0.80 (s, 3 H).
- 251 -MS
Ex.# m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.16 - 9.22 (m, 1 H), 7.66 - 7.73 (m, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.24 - 7.30 (m, 1 H), 7.04 - 7.14 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.83 (br d, J=7.1 Hz, 1 147 643.0 H), 4.30 -4.75 (m, 4 H), 3.91 (br d, J=14.8 Hz, 4 H), 3.44 - 3.56 (m, 1 H), 3.06 - 3.19 (m, 1 H), 2.53 -2.86 (m, 3 H), 2.29 - 2.52 (m, 6 H), 1.93 -2.27 (m, 5 H), 1.79- 1.92(m, 1H), 1.64- 1.76 (m, 1 H), 0.76 - 0.87 (m, 3 H).
1HNMR (500 MHz, METHANOL-d4) 6 ppm 9.22 (s, 1 H), 7.68 (dd, J=8.89, 5.90 Hz, 1 H), 7.23 - 7.34 (m, 2 H), 7.07 (s, 1 H), 5.21 - 5.42 (m, 1 H), 4.52 (br d, J=12.33 Hz, 1 H), 4.24 - 4.36 (m, 611.2 3 H), 3.55 -3.68 (m, 1 H), 3.42 - 3.50 (m, 1 H), 3.20 - 3.29 (m, 3 H), 3.00 -3.09 (m, 1 H), 2.44 -2.52 (m, 1 H), 2.12 -2.39 (m, 6 H), 1.83 -2.05 (m, 5 H), 1.75 - 1.82 (m, 2H), 0.82 (dt, J=11.22, 7.43 Hz, 3 H).
1HNMR (500 MHz, METHANOL-d4) 6 ppm 9.22 (s, 1 H), 7.68 (dd, J=8.95, 5.84 Hz, 1 H), 7.31 (d, J=2.47 Hz, 1 H), 7.26 (t, J=9.34 Hz, 1 H), 7.07 (s, 1 H), 5.24 - 5.40 (m, 1 H), 4.53 (br d, J=9.86 Hz, 1 H), 4.25 - 4.37 (m, 3 H), 3.57 - 3.68 (m, 1 H), 3.43 -177 611.2 3.50 (m, 1 H), 3.18 -3.29 (m, 3 H), 3.00 - 3.07 (m, 1 H), 2.49 (br dd, J=14.34, 7.20 Hz, 1 H), 2.33 - 2.39 (m, 1 H) 2.12 - 2.31 (m, 5 H) 1.84 - 2.05 (m, 5 H), 1.76 - 1.83 (m, 2 H), 0.82 (q, J=7.14 Hz, 3 H).
5-Ethyl-6-fluoro-4-(8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxy-3-methylpiperidin-l-yl)pyrido[4,3-cipyrimidin-7-y1)naphthalen-2-ol (Example 148) OH
N ===== N HATU N ===== N
Pr2NEt DMA
OH OH
Example 148 7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-ol (80 mg, 0.16 mmol, Intermediate D) was dissolved in N,N-dimethylacetamide (1.3 mL), HATU
(0.24 mg, 0.63 mmol) and N,N-diisopropylethylamine (0.10 g, 0.14 mL, 0.78 mmol) and 3-methoxy-3-
- 252 -methylpiperidine (41 mg, 0.31 mmol, Enamine) were added and the mixture was stirred at rt overnight. Water (0.5 mL) was added and the mixture was stirred overnight. The crude residue was purified by reverse phase HPLC to yield 5-ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxy-3-methylpiperidin-l-yOpyrido[4,3-alpyrimidin-7-yl)naphthalen-2-ol as TFA salt and as off-white solid (16 mg, 22 iamol, 14 % yield). m/z (ESI): 622.0 (M+H)+. 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.28 - 9.40 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.32 - 7.38 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.07 -7.11 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.51 -4.75 (m, 3 H), 3.83 -4.15 (m, 3 H), 3.35 -3.75 (m, 4 H), 3.11 -3.23 (m, 3 H), 2.53 -2.83 (m, 2 H), 2.31 -2.53 (m, 4 H),2.11 - 2.28 (m, 3 H), 1.95 - 2.10 (m, 1H), 1.61 - 1.85 (m, 2 H), 1.27 (d, J=7.3 Hz, 3 H), 0.78 - 0.86 (m, 3 H).
Table 11: Examples 149 to 161. prepared in an analogous manner to Example 148.
Ex. Salt Method Structure Name Reagent Form Change z__µcF 4-(4-(4,4- 2,2,2- 4,4-Difluoroazepan- trifluo difluoroazepa 1-y1)-8-fluoro-2- roacet ne F (42R,7aS)-2- ate hydrochlorid fluorotetrahydro-N 0 e (CAS#:
N 1H-pyrrolizin- 1094073-72-OH
7a(5H)- 9, Combi-yl)methoxy)pyrid Blocks Inc.) o[4,3-al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol 150 o F
< 1-(7-(8-Ethy1-7- 2,2,2- 5,5-fluoro-3- trifluo difluoroazepa \***.N'j hydroxynaphthal roacet n-4-one F en-1-y1)-8-fluoro- ate hydrochlorid '*NL 2-(42R,7aS)-2-N 0 e (CAS#:
N fluorotetrahydro- 2097991-20-OH 1H-pyrrolizin- 1, Enamine) 7a(5H)-yl)methoxy)pyrid o[4,3-al pyrimidin-4-
- 253 -y1)-5,5-difluoroazepan-4-one CN 1-(7-(8-Ethy1-7- Free 3- Purificatio fluoro-3- base cyanopiperidi n was F hydroxynaphthal ne (CAS#: performed NI \ N en-1-y1)-8-fluoro- 7492-88-8, with 0.1%
N 0 2-(((2R,7aS)-2- Combi formic fluorotetrahydro- Blocks) acid in OH 1H-pyrrolizin- H20 and 7a(511)- MeCN as yl)methoxy)pyrid mobile o[4,3- phase, cUpyrimidin-4- XSelect yl)piperidine-3- column carbonitrile (19 xl mm, 5 um) 152 1-(7-(8-Ethy1-7-2,2,2- 3,3-difluoro-F fluoro-3- trifluo 4-hydroxynaphthal roacea piperidinone F en-1-y1)-8-fluoro- te hydrochlorid N N
I 2-(42R,7aS)-2- e (CAS#:
N 0 N fluorotetrahydro- 1283720-75-1H-pyrrolizin- 1, Advanced OH 7a(5H)- ChemBlocks yl)methoxy)pyrid Inc.) o[4,3-d] pyrimidin-4-y1)-3,3-difluoropiperidin-4-one
- 254 -153 OH 1-(7-(8-Ethy1-7- 2,2,2- piperidin-4-ol fluoro-3- trifluo (CAS#:
hydroxynaphthal roacea 5382-16-1, F en-l-y1)-8-fluoro- te Combi-õI 2-(42R,7aS)-2- Blocks Inc.) fluorotetrahydro-1H-pyrrolizin-OH 7a(511)-yl)methoxy)pyrid o[4,3-al pyrimidin-4-yl)piperidin-4-ol 154 F3c.õ,cyoH (3R,55)-1-(7-(8- 2,2,2- (3R,55)-5-F Ethyl-7-fluoro-3- trifluo (trifluoromet F hydroxynaphthal roacea hyl)piperidin-N === N
I en-l-y1)-8-fluoro- te 3-ol (CAS#:
N 2-(((2R,7aS)-2- 2227198-76-fluorotetrahydro- 5, AA
OH
1H-pyrrolizin- Blocks) 7a(5H)-yl)methoxy)pyrid 0[4,3 -al pyrimidin-4-y1)-5-(trifluoromethyl) piperidin-3-ol 6-(7-(8-Ethy1-7- 2,2,2-fluoro-3- trifluo azabi 6-cyclo[3.
hydroxynaphthal roacea 2.11octan-2-F
F en-1-y1)-8-fluoro- te ol (CAS#:
N q 2-(((2R,7aS)-2- 1934420-45-..===
N N fluorotetrahydro- 7, Enamine) 1H-pyrrolizin-OH 7a(5H)-yl)methoxy)pyrid 0[4,3 -al pyrimidin-4-y1)-6-azabicyclo [3.2.1]
octan-2-ol
- 255 -F F 1-(7-(8-Ethy1-7- 2,2,2- 3 -r/OH fluoro-3- trifluo (trifluoromet hydroxynaphthal roacea hyl)piperidin-F en-1-y1)-8-fluoro- te 3-ol (CAS#:
= \ N 2-(((2R,7aS)-2-N*Le"4 fluorotetrahydro-7, Enamine) 1H-pyrrolizin-OH 7a(511)-yl)methoxy)pyrid o[4,3-al pyrimidin-4-y1)-3-(trifluoromethyl) piperidin-3-ol 157 3-Cyclopropy1-1- 2,2,2- 3-dON (7-(8-ethyl-7-trifluo cyclopropylpi fluoro-3- roacea peridin-3-ol hydroxynaphthal te (CAS#:
N NN
I en-1-y1)-8-fluoro- 1494822-71-N 2-(((2R,7aS)-2- 7, Enamine) fluorotetrahydro-OH 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrid o[4,3-d] pyrimidin-4-yl)piperidin-3-ol a NH, 158 o 1-(7-(8-Ethy1-7- 2,2,2- azepane-3-s:
fluoro-3- trifluo sulfonamide hydroxynaphthal roacea (CAS#:
N NN F en-1-y1)-8-fluoro- te i 2-(((2R,7aS)-2- 9, fluorotetrahydro- Chemspace) OH
1H-pyrrolizin-7a(5H)-yl)methoxy)pyrid o[4,3-al pyrimidin-4-ypazepane-3-sulfonamide
- 256 -159HO 1-(7-(8-Ethy1-7- 2,2,2- 3-NH2 fluoro-3- trifluo hydroxypiper hydroxynaphthal roacea idine-3-ir N F en-1-y1)-8-fluoro- te carboxamide õI 2-(42R,7aS)-2- hydrochlorid fluorotetrahydro- e (CAS#:
1H-pyrrolizin- 1803570-33-OH 7a(511)- 3, Aurum yl)methoxy)pyrid Pharmatech o[4,3- LLC) al pyrimidin-4-y1)-3-hydroxypiperidin e-3-carboxamide 160 ,,,, rro.OH rel-(3R,5R)-1-(7- 2,2,2-rac-(3R,5R)-(8-Ethyl-7- trifluo 5-NLO
F LN) F fluoro-3- roacea methylpiperi *
hydroxynaphthal te din-3-ol N en-l-y1)-8-fluoro- (CAS#:
F
2-(((2R,7aS)-2- 1354392-05-OH
fluorotetrahydro- 4, 1H-pyrrolizin- Chem Space) 7a(5H)-yl)methoxy)pyrid o[4,3-cil pyrimidin-4-y1)-5-methylpiperidin-3-ol 161 otp 4-(4-(3- 2,2,2- 3-`si F
y ((Difluoromethyl trifluo ((difluoromet N F )sulfonyl)piperidi roacea hyl)sulfonyl) N ' N F n-1-y1)-8-fluoro- te piperidine I N*Le,65 2-(42R,7aS)-2- hydrochlorid N fluorotetrahydro- e (CAS#: of 1H-pyrrolizin- free base:
OH
7a(5H)- 1783321-40-yl)methoxy)pyrid 3, o[4,3- ChemSpace) al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol
- 257 -Table 12. Analytical Data of Examples 149 to 161.
MS
Ex.
m/z (ESI): 111 NMR
(M+H)+
1H NMR (METHANOL-d4, 400 MHz) 6 9.26 (s, 1H), 7.71 (dd, 1H, J=5.9, 9.0 Hz), 7.36 (d, 1H, J=2.7 Hz), 7.28 (t, 1H, J=9.4 Hz), 149 628.0 7.11 (d, 1H, J=2.5 Hz), 5.5-5.7 (m, 1H), 4.79 (s, 1H), 4.7-4.7 (m, 1H), 4.2-4.3 (m, 4H), 3.8-4.1 (m, 3H), 3.4-3.6 (m, 1H), 2.3-2.8 (m, 8H), 2.1-2.3 (m, 6H), 0.83 (dt, 3H, J=1.6, 7.3 Hz).
1H NMR (METHANOL-4, 400 MHz) 6 9.1-9.3 (m, 1H), 7.69 (dd, 1H, J=5.9, 9.0 Hz), 7.32 (d, 1H, J=2.5 Hz), 7.26 (t, 1H, J=9.4 660.0 Hz), 7.0-7.1 (m, 1H), 5.4-5.7 (m, 1H), 4.6-4.7 (m, 2H), 4.20 (dt, (M+H30)+ 2H, J=6.1, 11.0 Hz), 3.8-4.1 (m, 5H), 3.5-3.6 (m, 2H), 2.99 (br dd, 1H, J=6.2, 8.7 Hz), 2.6-2.7 (m, 3H), 2.3-2.5 (m, 5H), 2.1-2.3 (m, 2H), 0.8-0.9 (m, 3H).
1HNMR (500 MHz, DMSO-d6) 6 ppm 9.20 (d, J=1.2 Hz, 1 H), 7.74 - 7.82 (m, 1 H), 7.33 - 7.38 (m, 2 H), 7.00 - 7.05 (m, 1 H), 151 603.2 5.50 - 5.64 (m, 1 H), 4.56 - 4.68 (m, 2 H), 4.33 -4.48 (m, 1 H), 4.12 - 4.24 (m, 1 H), 4.01 -4.10 (m, 1 H), 3.70 - 3.92 (m, 3 H), 1.78 -2.41 (m, 9 H), 0.66 - 0.76 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.17 - 9.23 (m, 1 H), 7.66 - 7.74 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.24 - 7.32 (m, 1 H), 646.0 7.06 -7.11 (m, 1 H), 5.51 - 5.70 (m, 1 H), 4.67 -4.77 (m, 2 H), (M+H30)+ 4.37 -4.53 (m, 2 H), 4.13 - 4.32 (m, 2 H), 3.84 - 4.11 (m, 3 H), 3.45 -3.58 (m, 1 H), 2.55 -2.83 (m, 2 H), 2.31 -2.53 (m, 4 H), 2.09 - 2.29 (m, 4 H), 0.76 - 0.86 (m, 3 H).
1HNMR (400 MHz, METHANOL-d4) 6 ppm 9.11 - 9.17 (m, 1 H), 7.70 (s, 1 H), 7.32 - 7.37 (m, 1 H), 7.23 - 7.32 (m, 1 H), 7.05 -7.11 (m, 1 H), 5.48 -5.71 (m, 1 H), 4.63 -4.75 (m, 2 H), 4.37 -153 594.0 4.51 (m, 2 H), 3.82 - 4.15 (m, 6 H), 3.43 -3.56 (m, 1 H), 2.55 -2.82 (m, 2 H), 2.31 - 2.55 (m, 4 H), 2.07 - 2.29 (m, 4 H), 1.72 -1.89 (m, 2 H), 0.75 - 0.89 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.16 - 9.23 (m, 1 H), 7.67 - 7.74 (m, 1 H), 7.32 - 7.38 (m, 1 H), 7.23 - 7.32 (m, 1 H), 7.05 - 7.11 (m, 1 H), 5.49 - 5.73 (m, 1 H), 4.82 - 4.91 (m, 1 H), 154 662.0 4.68 - 4.77 (m, 3 H), 3.84 - 4.11 (m, 4 H), 3.45 -3.57 (m, 1H), 3.35 -3.43 (m, 1 H), 3.25 - 3.30 (m, 1 H), 2.84 - 3.03 (m, 1 H), 2.56 -2.80 (m, 2 H), 2.32 - 2.53 (m, 5 H), 2.13 - 2.30 (m, 2 H), 1.61 - 1.81 (m, 1 H), 0.82 (s, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.15 - 9.59 (m, 1 H), 7.66 - 7.76 (m, 1 H), 7.33 - 7.38 (m, 1 H), 7.23 - 7.32 (m, 1 H), 155 6200. 7.04 - 7.13 (m, 1 H), 5.47 - 5.69 (m, 1 H), 4.94 -5.12 (m, 1H), 4.59 - 4.77 (m, 2 H), 3.81 - 4.32 (m, 6 H), 3.43 - 3.57 (m, 1H), 2.31 -2.85 (m, 8 H), 2.12 -2.30 (m, 3 H), 1.59 -2.09 (m, 3 H), 1.20 - 1.44 (m, 1 H), 0.75 - 0.89 (m, 3 H).
- 258 -MS
Ex.
m/z (ESI): 1H NMR
(M+H)+
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.27 - 9.36 (m, 1 H), 7.67 -7.74 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.06 -7.10 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.65 -4.77 (m, 4 H), 156 622.8 3.69 - 4.11 (m, 4 H), 3.40 - 3.55 (m, 2 H), 2.54 - 2.81 (m, 2 H), 2.31 -2.51 (m, 4 H), 2.14 -2.31 (m, 3 H), 2.05 -2.13 (m, 2 H), 1.87 - 1.99 (m, 1 H), 0.77 - 0.88 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.31 - 9.41 (m, 1 H), 7.66 -7.74 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 7.07 -7.11 (m, 1 H), 5.49 - 5.69 (m, 1 H), 4.63 -4.75 (m, 3 H), 157 634.9 4.36 - 4.48 (m, 1 H), 3.83 -4.11 (m, 3 H), 3.63 -3.74 (m, 1 H), 3.39 -3.55 (m, 2 H), 2.54 -2.83 (m, 2 H), 2.31 -2.51 (m, 4 H), 2.08 -2.30 (m, 3 H), 1.80- 1.92 (m, 3 H), 0.92- 1.04 (m, 1 H), 0.83 (s, 3 H), 0.30 - 0.57 (m, 4 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.12 - 9.34 (m, 1 H), 7.65 -7.76 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.22 - 7.31 (m, 1 H), 7.01 -7.11 (m, 1 H), 5.50 - 5.71 (m, 1 H), 4.96 - 5.13 (m, 1 H), 158 671.2 4.80 -4.94 (m, 2 H), 4.27 - 4.41 (m, 1 H), 4.13 - 4.26 (m, 1 H), 3.82 - 4.13 (m, 4 H), 3.64 - 3.80 (m, 1 H), 3.44 - 3.58 (m, 1 H), 2.03 -2.86 (m, 12 H), 1.83 - 1.98 (m, 1 H), 1.37 - 1.57 (m, 1 H), 0.74 - 0.90 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.28 - 9.38 (m, 1 H), 7.65 -7.75 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.23 - 7.31 (m, 1 H), 159 637.2 7.05 -7.12 (m, 1 H), 5.48 - 5.70 (m, 1 H), 4.63 -4.75 (m, 3 H), 4.44 - 4.55 (m, 1 H), 3.83 - 4.11 (m, 4 H), 3.46 - 3.58 (m, 2 H), 2.54 - 2.82 (m, 2 H), 2.29 - 2.52 (m, 5 H), 2.11 -2.28 (m, 3 H), 1.88 - 1.99 (m, 2 H), 0.76 - 0.88 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.28 - 9.37 (m, 1 H), 7.66 - 7.74 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.04 - 7.11 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.60 - 4.75 (m, 4 H), 160 607.9 4.20 (br s, 1 H), 3.91 (br d, J=15.0 Hz, 3 H), 3.61 -3.78 (m, 1 H), 3.44 - 3.56 (m, 1 H), 2.95 -3.17 (m, 1 H), 2.54 - 2.81 (m, 2 H), 2.39 (br d, J=6.1 Hz, 5 H), 2.14 - 2.29 (m, 2 H), 1.97 - 2.06 (m, 1 H), 1.55 - 1.67 (m, 1 H), 1.02 - 1.11 (m, 3 H), 0.77 - 0.88 (m, 3 H).
1HNMR (400 MHz, METHANOL-4) 6 ppm 9.17 - 9.22 (m, 1 H), 7.65 -7.75 (m, 1 H), 7.31 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 7.05 - 7.11 (m, 1 H), 6.70 - 7.02 (m, 1 H), 5.50 - 5.71 (m, 1 H), 161 692.0 4.67 -4.76 (m, 1 H), 4.21 - 4.35 (m, 1 H), 4.02 - 4.14 (m, 1 H), 3.88 -4.01 (m, 4 H), 3.45 - 3.57 (m, 1 H), 3.07 (s, 1 H), 2.94 (s, 1 H), 2.56 -2.84 (m, 2 H), 2.33 -2.52 (m, 5 H), 2.12 -2.32 (m, 4 H), 2.09 (s, 1 H), 1.82 - 1.95 (m, 1 H), 0.76 - 0.85 (m, 3 H).
- 259 -(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (Example 162) o o CfANH, 0,11-NH, N
H
F S F N F N
F 6-5 PcaPP63/4 F F N s.. s=N N
*s. s= N
arm 1 ..... FICIm/demoxaHne I NI*LOW
(101 F N 1,4-thoxane F F

s..., *s. Step 1 s.....= s.. Step 2 OH
Example 162 Step 1: (R)-1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide. A vial was charged with 7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(methylthio)pyrido[4,3-cilpyrimidine (20 mg, 0.034 mmol), copper(I) thiophene-2-carboxylate (13 mg, 0.068 mmol), Pd(PPh3)4 (4.0 mg, 3.42 [tmol), and (R)-piperidine-3-carboxamide (8.8 mg, 0.068 mmol). The solids were suspended in degassed 1,4-dioxane (0.17 mL), and the reaction was capped and stirred at 90 C. After stirring overnight, the reaction was absorbed onto a silica plug and purified via column chromatography on silica gel, eluting with a gradient of 0-100% of 3:1 Et0Ac/Et0H blend in heptane with 2% triethylamine additive to provide (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)piperidine-3-carboxamide, which was used directly in the subsequent step. m/z (ESI): 666.0 (M+H)+.
Step 2: (R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidine-3-carboxamide. Synthesized in an analogous manner to Example 1. The product was isolated as TFA salt (9.0 mg, 0.11 mmol, 31 % yield over 2 steps). m/z (ESI): 621.2 (M+H)+. II-I NMR (400 MHz, METHANOL-d4) 6 ppm 9.15 (d, J=1.88 Hz, 1 H) 7.71 (br d, J=9.20 Hz, 1 H) 7.34 (d, J=2.51 Hz, 1 H) 7.23 -7.30 (m, 1 H) 7.08 (s, 1 H) 5.47 - 5.70 (m, 1 H) 4.74 (br s,3 H) 4.38 - 4.51 (m, 1 H) 3.71 -4.13 (m, 5 H)
- 260 -3.42 - 3.57 (m, 1 H) 2.53 - 2.83 (m, 3 H) 2.32 -2.52 (m, 4 H) 2.13 - 2.29 (m, 3 H) 1.97 - 2.10 (m, 2 H) 1.77 - 1.94 (m, 1 H) 0.76 - 0.86 (m, 3 H).
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yl)methoxy)pyrido14,3-d]pyrimidin-4-y1)-methylpiperidine-3-carboxamide (Example 163 and Example 164) H2N)LCy OH
Synthesized in an analogous manner to Example 162, using 5-methylpiperidine-3-carboxamide hydrochloride (CAS#: 2228678-05-3, Enamine). Isomer 1 (Example 163) was isolated as bis(2,2,2-trifluoroacetate) and as light-yellow solid. m/z (ESI):
635.3 (M+H)+.
NMR (400 MHz, METHANOL-4) 6 ppm 9.14 (d, J=1.67 Hz, 1 H) 7.70 (s, 1 H) 7.34 (d, J=2.51 Hz, 1 H) 7.27 (s, 1 H) 7.07 (d, J=1.88 Hz, 1 H) 5.48 - 5.70 (m, 1 H) 4.39 - 4.69 (m, 3 H) 3.64 -4.15 (m, 5 H) 3.43 - 3.57 (m, 1 H) 2.76 (s, 6 H) 2.34 -2.52 (m, 4 H) 2.13 -2.30 (m, 3 H) 1.76 - 2.10 (m, 3 H) 0.76 - 0.87 (m, 3 H). Isomers 2 (Example 164) was isolated as bis(2,2,2-trifluoroacetate) and as light-yellow solid. m/z (ESI): 635.3 (M+H)+. 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.12 (s, 1 H) 7.68 - 7.74 (m, 1 H) 7.34 (d, J=2.72 Hz, 1 H) 7.23 -7.31 (m, 1 H) 7.05 - 7.10 (m, 1 H) 5.51 -5.71 (m, 1 H) 4.81 -4.96 (m, 3 H) 4.57 -4.71 (m, 2 H) 3.87 - 4.15 (m, 3 H) 3.40 - 3.58 (m, 1 H) 3.03 - 3.16 (m, 1 H) 2.53 -2.89 (m, 3 H) 2.32 - 2.53 (m, 4 H) 2.13 - 2.29 (m, 3 H) 1.97 - 2.10 (m, 1 H) 1.51 - 1.65 (m, 1 H) 1.06- 1.12 (m, 3 H) 0.78 - 0.86 (m, 3 H).
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (Example 165)
-261 -ot o CI

N HCI
1%11 F

1:61 F No;) =
CH2Cl2 * F No;) MeCN
OTIPS OTIPS
Step 1 Step 2 Ovip 0 0 dS,NH2 TBAF
*N N F F N N
THF
* F N 0 Step 3 I

*
OTIPS OH
Example 165 Step 1: 4-Chloro-7-(7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-l-y1)-8-fluoro-2-1((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 7-(7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yOmethoxy)-4-(methylthio)pyrido[4,3-dlpyrimidine (54 mg, 0.079 mmol) in DCM (1 mL) at 0 C
was added sulfuryl chloride (1.0 M in DCM, 0.24 mL, 0.24 mmol) slowly. The reaction mixture was stirred at 0 C for 1 h. The reaction mixture was concentrated under reduced pressure and the crude product was used directly in the subsequent step. m/z (ESI): 676.0 (M+H)+.
Step 2: (R)-1-(7-(7,8-Difluoro-3-((triisopropylsilypoxy)naphthalen-l-y1)-8-fluoro-2-1((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. A mixture of 4-chloro-7-(7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidine (26 mg, 0.039 mmol), (3R)-piperidine-3-sulfonamide hydrochloride (16 mg, 0.078 mmol), and Hunig's base (15 mg, 0.02 mL, 0.12 mmol) was stirred in acetonitrile (0.5 mL) at rt for 30 min. The reaction mixture was purified by reverse phase HPLC to afford (R)-1-(7-(7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-
- 262 -pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-yl)piperidine-3-sulfonamide (5.0 mg, 6.23 umol, 16 % yield) as white solid. m/z (ESI): 803.2 (M+H)+.
Step 3: (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. To a solution of (R)-1-(7-(7,8-difluoro-3-((triisopropylsilypoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yl)piperidine-3-sulfonamide (5.0 mg, 6.23 umol) in tetrahydrofuran (0.5 mL) at 0 C was added tetrabutylammonium fluoride solution (1.0 M in THF, 16 mg, 0.018 mL, 0.062 mmol) slowly. The resulting mixture was stirred at 0 C for 0.5 h. The reaction mixture was purified twice by reverse phase HPLC to afford (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yOpiperidine-3-sulfonamide as TFA salt (2.0 mg, 2.3 umol, 37 % yield) as light yellow solid.
m/z (ESI):
647.0 (M+H)+. 1HNMR (400 MHz, METHANOL-4) 8 ppm 9.20 (s, 1 H), 7.64 (ddd, J=9.1, 4.9, 1.5 Hz, 1 H), 7.36 - 7.46 (m, 2 H), 7.28 (d, J=9.8 Hz, 1 H), 5.50 - 5.73 (m, 1 H), 5.02 (br d, J=13.2 Hz, 1 H), 4.77 -4.84 (m, 2 H), 4.56 -4.66 (m, 1 H), 3.73 -4.14 (m, 5 H), 3.46 -3.57 (m, 2 H), 2.54 - 2.84 (m, 2 H), 2.33 - 2.49 (m, 4 H), 2.04 - 2.26 (m, 3 H), 1.79 - 1.92 (m, 1H).
4-(4-(Azepan-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol (Example 166) FO
\ N65 * F
OH
Example 166 Synthesized in an analogous manner to Example 165 using azepane (CAS#: 111-49-9, Sigma-Aldrich Corporation). The product was isolated as its TFA salt. m/z (ESI, +ve ion):
582.0 (M+H)+. 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.23 (s, 1 H), 7.65 (ddd, J=9.2,
- 263 -4.8, 1.7 Hz, 1 H), 7.36 - 7.46 (m, 2 H), 7.28 (d, J=2.3 Hz, 1 H), 5.47 - 5.71 (m, 1 H), 4.60 -4.74 (m, 2 H), 4.11 -4.22 (m, 4 H), 3.84 - 4.02 (m, 3 H), 3.46 - 3.53 (m, 1 H), 2.53 -2.82 (m, 2 H), 2.33 -2.48 (m, 3 H), 2.13 -2.24 (m, 1 H), 2.04 -2.13 (m, 4 H), 1.71 -1.79 (m, 4 H).
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(02R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol (Example 167) HO,BõOH
Cf OH LOH
1. PCy3 Pd G2, K3PO4 C
, 11 I1 F 1:61 THF/H20 N
2. HCl/1,4-dioxane )P c-cNI01( OH
Example 167 (R)-1-(7-(8-Chloro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol (46 mg, 0.07 mmol, synthesized in an analogous manner to Example 1 using 248-chloro-3-(methoxyrnethoxy)- -naphth al enyl I -4,4,5,5-tetram ethyl-I .3,2-dioxaborolane, CAS#: 2621938-40-5, LabNetwork) was suspended in toluene (0.7 mL) and water (0.04 mL). Cyclopropylboronic acid (7.4 mg, 0.09 mmol), PCy3 Pd G2 (4.0 mg, 7.0 mop and potassium phosphate, monohydrate (66 mg, 0.29 mmol) were added. The mixture was degassed for 5 minutes and then stirred at 80 C for 16 h. The crude mixture was purified by reverse phase HPLC. The product obtained was dissolved in THF (1.5 mL). HC1 (4 M in 1,4-dioxane, 0.5 mL) was added and the mixture was stirred at rt for 2 h.
Volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield (R)-1-(7-(8-cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-methylpiperidin-3-ol (5.5 mg, 9.14 ma 13% yield). m/z (ESI): 602.2 (M+H)+.
NMR
(400 MHz, METHANOL-4) 6 ppm 9.23 - 9.33 (m, 1 H), 7.65 (s, 1 H), 7.31 - 7.39 (m, 2 H), 7.19 -7.25 (m, 1 H), 7.07 - 7.13 (m, 1 H), 5.50 -5.69 (m, 1 H), 4.57 -4.74 (m, 3 H), 4.31 -4.43 (m, 1 H), 3.86 -4.12 (m, 3 H), 3.40 - 3.71 (m, 4 H), 2.53 -2.84 (m, 2 H), 2.31 -2.50 (m,
- 264 -3 H), 2.12 - 2.27 (m, 2 H), 1.76- 1.94 (m, 3 H), 1.55 - 1.68 (m, 1 H), 1.32 (d, J=7.3 Hz, 5 H), 0.53 - 0.72 (m, 1 H), 0.27 - 0.48 (m, 2 H).
(R)-1-(8-Chloro-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51/)-yl)methoxy)pyrido14,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol (Example 168) rpOH
e'65 CI
OH
Example 168 Synthesized in an analogous manner to Example 43 using 2,4,7,8-tetrachloropyrido[4,3-dlpyrimidine (CAS#: 2454396-63-3, LabNetwork) and (3R)-3-methylpiperidin-3-ol hydrochloride (CAS#: 2305080-34-4, PharmaBlock, Inc.).
The product was isolated as 2,2,2-trifluoroacetate and as light-yellow solid. m/z (ESI):
623.8 (M+H)+.
NMR (400 MHz, METHANOL-4) 6 ppm 9.35 - 9.43 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.30 -7.33 (m, 1 H), 7.23 - 7.30 (m, 1 H), 6.98 - 7.05 (m, 1 H), 5.48 - 5.68 (m, 1 H), 4.67 - 4.76 (m, 2 H), 4.59 -4.67 (m, 1 H), 4.30 -4.42 (m, 1 H), 3.98 -4.15 (m, 1 H), 3.84 -3.97 (m, 2 H), 3.58 -3.71 (m, 1 H), 3.40 - 3.56 (m, 2 H), 2.55 -2.82 (m, 2 H), 2.43 -2.53 (m, 1 H), 2.25 -2.42 (m, 4 H), 2.10 -2.24 (m, 2 H), 1.75 - 1.94 (m, 3 H), 1.31 (d, J=6.3 Hz, 3 H), 0.80 - 0.91 (m, 3 H).
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-0(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (Example 169) rpOH
V*65 OH
- 265 -Example 169 Synthesized in an analogous manner to Example 43 using 2,4,7-trichloro-8-methylpyrido[4,3-dlpyrimidine (CAS#: 2454396-72-4, WuXi App Tec Co. Ltd.) and (3R)-3-methylpiperidin-3-ol hydrochloride (CAS#: 2305080-34-4, PharmaBlock, Inc.).
The product was isolated as 2,2,2-trifluoroacetate and as white solid. m/z (ESI): 604.0 (M+H)+. 1HNMR
(400 MHz, METHANOL-4) 6 ppm 9.65 - 9.74 (m, 1 H), 7.73 - 7.82 (m, 1 H), 7.40 -7.48 (m, 1 H), 7.29 - 7.39 (m, 1 H), 7.13 - 7.19 (m, 1 H), 5.51 -5.73 (m, 1 H), 4.85 -4.91 (m, 1 H), 4.73 -4.80 (m, 2 H), 4.26 - 4.44 (m, 1 H), 3.83 -4.11 (m, 3 H), 3.55 -3.66 (m, 1 H), 3.45 - 3.55 (m, 1 H), 3.35 - 3.44 (m, 1 H), 2.57 - 2.87 (m, 2 H), 2.44 - 2.54 (m, 1 H), 2.35 - 2.44 (m, 3 H), 2.32 -2.35 (m, 4 H), 2.22 -2.31 (m, 1 H), 2.08 -2.20 (m, 1 H), 1.77 -1.96 (m, 3 H), 1.34 (d, J=2.7 Hz, 3 H), 0.87 (br d, J=4.4 Hz, 3 H).
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(02S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol bis(2,2,2-trifluoroacetate) (Example 178) OH 1. 0 HO ) L,OH
-11\1 HOACF3 KOtBu, THF
N N N

2. HCI, MeCN 0 N
N S

OMOM OH
Example 178 To an 8-mL vial was added ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (24 mg, 0.15 mmol, Pharmablock, Inc.) in THF (1.1 mL). The vial was then cooled to 0 C and potassium tert-butoxide, 1.0 M in THF (220 uL, 0.22 mmol) was added.
After stirring for 45 min, (3R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(methylsulfinyl)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (60 mg, 0.11 mmol, Intermediate Q) in tetrahydrofuran (1.1 mL) was added. After stirring at rt for 30 min, the reaction was quenched via the addition of saturated aqueous NH4C1 solution (2 mL) and water (2 mL). The mixture was then diluted with dichloromethane (5 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 5 mL) and the
- 266 -combined organic layers were dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a colorless oil. The crude oil was then purified via column chromatography on silica gel using a gradient of 0-70% of a3:1 Et0AciEt0H
(with 2%
triethylamine) in heptane, to provide crude (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42S,7aR)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol) as light yellow solid. m/z (ESI): 652.2 (M+H)+.
The crude (R)-1-(7-(8-ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-l-y1)-8-fluoro-2-(42S,7aR)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -cil pyrimidin-4-.. y1)-3-methylpiperidin-3-ol was dissolved in MeCN (3.4 mL) and 4 M HC1 in 1,4-dioxane (680 4, 2.69 mmol) was added. After stirring for 1 h at rt, the reaction was concentrated under reduced pressure and purified via reverse phase HPLC to provide (R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - cil pyrimidin-4-y1)-3-methylpiperidin-3-ol bis(2,2,2-trifluoroacetate) (11 mg, 0.014 mmo1,13 % yield) as light yellow solid. m/z (ESI): 608.2 (M+H)+. 1HNMR (400 MHz, METHANOL-4) 6 ppm 9.32 (s, 1 H) 7.65 - 7.75 (m, 1 H) 7.34 (d, J=2.51 Hz, 1 H) 7.28 (s, 1 H) 7.08 (s, 1 H) 5.49 - 5.71 (m, 1 H) 4.59 -4.78 (m, 3 H) 4.33 -4.45 (m, 1 H) 3.85 - 4.15 (m, 3 H) 3.57 - 3.72 (m, 1 H) 3.42 - 3.55 (m, 2 H) 2.52 - 2.83 (m, 2 H) 2.31 - 2.52 (m, 4 H) 2.11 - 2.30 (m, 3 H) 1.78 - 1.94 (m, 3 H) 1.33 (d, J=8.15 Hz, 3 H) .. 0.77 - 0.88 (m, 3 H).
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-((tetrahydro-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (Example 179).
Z,OH
===..
N N
N
OH
Example 179
- 267 -Synthesized in an analogous manner to Example 178 using 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (CAS#: 78449-72-6, Advanced ChemBlocks Inc.).
The product was isolated as 2,2,2-trifluoroacetate and as white solid. m/z (ESI):
590Ø 1HNMR
(400 MHz, METHANOL-4) 6 ppm 9.31 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34(d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.08 (t, J=2.2 Hz, 1 H), 4.69 (s, 3 H), 4.32 - 4.43 (m, 1 H), 3.58 - 3.79 (m, 4 H), 3.43 -3.52 (m, 1 H), 3.28 - 3.31 (m, 1 H), 2.31 -2.53 (m, 3 H), 2.11 -2.31 (m, 8H), 1.76 - 1.95 (m, 3 H), 1.32 (d, J=8.6 Hz, 3 H), 0.77-0.90(m, 3 H).
(R)-1-(24(14(Dimethylamino)methypcyclopropyl)methoxy)-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoropyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidin-3-ol (Example 180).
Z.OH
N N
I
)10 N
OH
Example 180 Synthesized in an analogous manner to Example 178 using (1-Rdimethylamino)methylicyclopropypmethanol (CAS#: 39943-41-4, Enamine) and Lithium bis(trimethylsilyl)amide in THF solution (1 M). The product was isolated as off-white solid.
m/z (ESI): 578.3 (M+H)+. 1HNMR (400 MHz, DMSO-d6) 6 ppm 9.91 (d, J=2.5 Hz, 1 H), 9.27 (s, 1 H), 7.77 (dd, J=9.0, 6.1 Hz, 1 H), 7.27 - 7.42 (m, 2 H), 7.03 (d, J=2.5 Hz, 1 H), 4.72 (d, J=1.9 Hz, 1 H), 4.22 -4.46 (m, 3 H), 4.09 (br dd, J=19.8, 13.3 Hz, 1 H), 3.50 - 3.72 (m, 1 H), 3.30 - 3.45 (m, 3 H), 3.04 - 3.21 (m, 1 H), 2.69 - 2.88 (m, 5 H), 2.28 -2.41 (m, 1 H), 2.10 - 2.23 (m, 1 H), 1.95 - 2.07 (m, 1 H), 1.61- 1.79 (m, 3 H), 1.19 (d, J=9.4 Hz, 3 H), 0.86 (br s, 2 H), 0.67 - 0.80 (m, 5 H).
Biological Evalution Provided in this section is the biological evaluation of the specific examples provided herein.
- 268 -KRAS G12D TR-FRET Assay Compounds of interest were prepared in a dose-response titration in DMSO, and nL were added via Labcyte Echo to each well of a 384-well plate (Perkin Elmer 6008280).
The His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in Assay Buffer (20 mM
HEPES, pH 7.4, 10 mM MgCl2, 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 [LM GDP) and 2 uL was added to the appropriate wells of the 384-well plate. The plate was incubated for 30 minutes at room temperature. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 [LL was added to all wells and incubated for 1 hour at room temperature. Detection Reagent (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA)) was prepared in Assay Buffer, then 4 uL was added to the plate and incubated for 1 hour at room temperature. Plates were read using PerkinElmer EnVision (ex: 320 nm, eml: 665 nm, em2: 615 nm) and eml/em2 data was used to generate curve fits using a 4-parameter logistic model to calculate ICso values.
KRAS G12D Coupled Nucleotide Exchange Assay Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and C118A
amino acid substitutions and an N-terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, and 0.01% Triton X-100) with a compound dose-response titration for 2 hours. Following compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA
acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen0 technology, and data were analyzed using a 4-parameter logistic model to calculate ICso values.
Phospho-ERK1/2 MSD Assay AsPC-1 (ATCCO CRL1682TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher
- 269 -Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37 C, 5% CO2. A
compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 C, 5% CO2 for 2 hours. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca2+ or Mg2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM
Tris-HC1 pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERK1/2 Whole Cell Lysate kits (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate ICso values.
Table 13: Biochemical and cellular activity of examples.

G12D2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (uM) ICso ULM) 1 0.001 0.002 0.165 2 0.001 0.001 0.115 3 0.009 0.006 >10 4 0.021 0.008 >10 5 0.019 0.010 NT
6 0.055 0.025 >10 7 0.037 0.025 >10 8 0.082 0.039 >10 9 0.005 0.005 1.340 10 0.002 0.002 NT
- 270 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 11 0.003 0.003 >10 12 0.002 0.003 0.377 13 0.002 0.004 0.107 14 0.012 0.007 1.100 15 0.017 0.012 1.480 16 0.031 0.013 2.860 17 0.038 0.039 3.180 18 0.003 0.003 0.105 19 0.026 0.034 NT
20 0.039 0.044 NT
21 0.032 0.032 NT
22 0.004 0.007 0.297 23 0.031 0.034 2.380 24 0.002 0.003 0.014 25 0.011 0.015 NT
26 0.004 0.006 NT
27 0.006 0.007 1.030 28 0.001 0.002 0.036 29 0.001 0.002 0.031 30 0.003 0.003 0.399 31 0.002 0.003 0.032 32 0.009 0.010 NT
33 0.013 0.008 NT
34 0.054 0.027 NT
-271 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 35 0.025 0.019 NT
36 0.007 0.005 0.344 37 0.042 0.023 NT
38 0.002 0.003 0.005 39 0.002 0.002 0.013 40 0.015 0.012 0.571 41 0.001 0.002 0.025 42 0.038 0.034 0.810 43 0.004 0.004 NT
44 0.004 0.008 NT
45 0.025 0.030 2.960 46 0.003 0.006 0.213 47 0.002 0.005 0.222 48 0.01 0.013 0.341 49 0.017 0.026 0.991 50 0.008 0.010 NT
51 0.025 0.019 NT
52 0.001 0.002 0.008 53 0.001 0.003 0.013 54 0.003 0.006 0.116 55 0.003 0.006 0.259 56 0.001 0.002 0.033 57 0.002 0.003 0.115 58 0.001 0.001 0.009
- 272 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 59 0.001 0.002 0.033 60 0.002 0.003 0.330 61 0.005 0.004 NT
62 0.04 0.042 NT
63 0.039 0.039 NT
64 0.006 0.005 NT
65 0.003 0.005 0.153 66 0.018 0.016 0.754 67 0.019 0.022 0.816 68 0.008 0.010 1.690 69 0.036 0.038 NT
70 0.032 0.035 NT
71 0.024 0.023 1.170 72 0.034 0.020 3.240 73 0.004 0.004 NT
74 0.007 0.006 2.710 75 0.027 0.035 NT
76 0.016 0.017 1.100 77 0.027 0.030 1.530 78 0.001 0.000 0.244 79 0.005 0.007 2.190 80 0.002 0.003 0.253 81 0.019 0.008 1.160 82 0.033 0.027 >10
- 273 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 83 0.002 0.003 >10 84 0.005 0.007 1.290 85 0.037 0.015 >10 86 0.064 0.022 >10 87 0.063 0.028 >10 88 0.006 0.002 >10 89 0.009 0.011 >3 90 0.016 0.008 NT
91 0.007 0.008 5.130 92 0.083 0.046 6.620 93 0.002 0.002 0.100 94 0.003 0.004 0.179 95 0.003 0.004 0.074 96 0.005 0.006 0.119 97 0.033 0.010 1.560 98 0.08 0.029 2.840 99 0.011 0.005 0.794 100 0.009 0.009 3.700 101 0.02 0.017 >10 102 0.002 0.002 1.900 103 0.004 0.007 NT
104 0.02 0.008 NT
105 0.009 0.008 0.939 106 0.01 0.007 NT
- 274 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 107 0.008 0.007 NT
108 0.011 0.007 NT
109 0.012 0.011 NT
110 0.006 0.011 NT
111 0.017 0.011 NT
112 0.012 0.009 NT
113 0.066 0.043 NT
114 0.011 0.008 NT
115 0.003 0.005 0.083 116 0.004 0.007 0.792 117 0.009 0.014 >10 118 0.003 0.002 0.105 119 0.035 0.017 NT
120 0.004 0.008 0.222 121 0.006 0.006 NT
122 0.033 0.013 NT
123 0.047 0.024 NT
124 0.07 0.037 NT
125 0.004 0.004 NT
126 0.037 0.024 3.340 127 0.002 0.003 0.008 128 0.002 0.003 0.293 129 0.001 0.004 0.064 130 0.004 0.006 NT
- 275 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 131 0.004 0.004 NT
132 0.001 0.001 0.119 133 0.002 0.004 0.661 134 0.002 0.019 0.259 135 0.001 0.002 0.081 136 0.01 0.014 0.614 137 0.002 0.002 0.040 138 0.016 0.013 >10 139 0.005 0.012 0.116 140 0.003 0.004 0.081 141 0.004 0.004 0.198 142 0.014 0.011 NT
143 0.062 0.036 >10 144 0.006 0.013 NT
145 0.008 0.008 0.593 146 0.002 0.002 0.233 147 0.015 0.013 0.714 148 0.038 0.041 NT
149 0.012 0.008 0.702 150 0.003 0.004 1.430 151 0.011 0.009 NT
152 0.004 0.006 2.670 153 0.004 0.007 0.353 154 0.016 0.022 NT
- 276 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.# Coupled Exchange Binding ICso ( M) 1 cells), ICso (AM) ICso (AM) 155 0.033 0.030 NT
156 0.001 0.002 0.172 157 0.017 0.016 1.240 158 0.002 0.004 1.420 159 0.002 0.003 3.080 160 0.003 0.004 0.414 161 0.076 0.049 NT
162 0.002 0.004 1.610 163 0.011 0.010 2.730 164 0.003 0.005 1.200 165 0.001 0.001 1.160 166 0.003 0.004 0.094 167 0.002 0.003 0.012 168 0.002 0.003 0.034 169 0.003 0.003 0.040 170 0.005 0.003 0.018 171 0.003 0.002 0.002 172 0.012 0.006 0.086 173 0.004 0.006 0.022 174 0.335 0.325 NT
175 0.008 0.005 0.01 176 0.005 0.003 0.005 177 0.024 0.012 0.109 178 0.005 0.003 0.008
- 277 -KRAS Gl2D
KRAS G12D 2 h p-ERK (AsPC-Ex.#
Binding ICso ( M) Coupled Exchange 1 cells), ICso (AM) ICso (AM) 179 0.005 0.002 0.018 180 0.003 0.003 0.012 NT: not tested.
REFERENCES
All references, for example, a scientific publication or patent application publication, cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims (55)

What is claimed is:
1. A compound of formula (I):
X
(Rx)pl im W
N N
Ri I

(I) or a pharmaceutically acceptable salt of said compound, wherein;
--- is a single bond or a double bond;
W is C, CH or N, wherein when W is CH or N, --- is a single bond;
X is CH2 or CH=CH;
n is 0, 1 or 2;
m is 0, 1 or 2;
p is 0, 1, 2, 3 or 4;
each II!' is hydroxyl, halogen, oxo, cyano, -N(W)2, C14 alkyl, Ci4 alkoxy, C1-haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 5-7 membered heteroaryl, -T-RY or two W taken .. together with adjacent carbon atoms can form C3-7 cycloalkyl, a 5-7 membered heterocycloalkyl, wherein each C3-7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of W or two II!' taken together can form a bridged ring where the bridge is selected from one of the following: -C14 alkylene, -C14 alkylene-O-C14 alkylene-, -0-, -S- or -C14 alkylene-S-C14 alkylene- and wherein each C1-4 alkylene is further substituted with 0-2 occurrences of RY;
L is C1-6 alkylene, alkylene, alkylene, NW, 0 or S, wherein each C1-6 alkylene, alkylene and -S-C1-6 alkylene chain is substituted with 0-2 occurrences of R2;
RI is hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycloalkyl substituted with .. 0-3 occurrences of R5;

R2 is halogen, hydroxyl, Ci_4 alkyl or two R2 on the same or adjacent carbon atoms can be taken together to form a C3_7 cycloalkyl;
R3 is aryl or heteroaryl substituted with 0-3 occurrences of R6;
R4 is hydrogen, hydroxyl, halogen, Ci4 alkyl, C14 alkoxy, Ci4 haloalkyl, C24 alkenyl, C24 alkynyl, C3_7 cycloalkyl or cyano;
each R5 is halogen, oxo, hydroxyl, amino or Ci4 alkyl;
each R6 is halogen, hydroxyl, cyano, -N(W)2, C14 alkyl, Ci4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C24 alkynyl or C3_6 cycloalkyl;
T is C1-4 alkylene, -S(0)2-, -C(0)-, -C14 alkylene-C(0)-, -N(H)-C(0)-, -N(H)-S(0)2-, Ci4 alkylene-S(0)2- or -S-;
RY is halogen, C1-4 alkyl, Ci4 alkoxy, Ci4 haloalkyl, hydroxyl, cyano or -N(W)2; and RZ is hydrogen or Ci4 alkyl.
2. The compound of claim 1, wherein L is -0-C1-6 alkylene (e.g., -0-methylene-, -0-ethylene- or -0-n-propylene) substituted with 0-2 occurrences of R2.
3. The compound of any of claims 1-2, wherein L is -0-ethylene or -0-n-propylene substituted with 0-2 occurrences of R2.
4. The compound of any of claims 1-3, wherein RI is hydroxyl or heterocycloalkyl substituted with 0-3 occurrences of R5.
5. The compound of any of claims 1-4, wherein R5 is halogen, cyano, C1-4 alkyl or oxo.
Ok
6. The compound of any of claims 1-5, wherein -L-R1 is F, `'µµOk F..01µ10k FlõCrOk C(Th 4c14E CN
40'"(3NH
H 4 HOok 100 or=
Sok N =*%%13)S
7. The compound of claim 6, wherein -L-R1 is 0 F.0 u = or =
8. The compound of any of claims 1-7, wherein R3 is aryl substituted with 0-occurrences of R6.
9. The compound of claim 8, wherein R3 is phenyl or naphthyl substituted with 0-3 occurrences of R6.
10. The compound of any of claims 1-7, wherein R3 is heteroaryl substituted with 0-3 occurrences of R6.
11. The compound of any of claims 8-10, wherein R6 is hydroxyl, halogen, C1-4 alkyl, CI-4 haloalkyl, C24 alkynyl, C3-6 cycloalkyl or
12. The compound of claim 11, wherein R6 is hydroxyl, methyl, ethyl, trifluoromethyl, difluoromethyl, ethynyl, fluorine, chlorine, cyclopropyl or -NH2.

* *
13. The compound of any of claims 1-12, wherein R3 is ON , OH , OH , A
rti re .41 40 110 &140 &140 OH , OH , OH , OH OH
CI V
it ill (6 CI CI Le CI
OH NH2 OH or HN-N
SI &el ill
14. The compound of claim 13, wherein R3 is OH , OH , OH , * *
OH , OH Or OH
15. The compound of any of claims 1-14, wherein W is N and --- is a single bond.
16. The compound of any of claims 1-15, wherein X is CH2.
17. The compound of claim 16, wherein n is 0 and m is 0; n is 1 and m is 0; or n is 0 and m is 1.
18. The compound of claim 17, wherein p is 0, 1 or 2.
19. The compound of claim 18, wherein each RX is hydroxyl, halogen, C14 alkyl, 5-7 membered heteroaryl, -T-Ry or two RX are taken together with adjacent carbon atoms to form __ a C3_7 cycloalkyl or 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of RY.
20. The compound of claim 18, wherein each RX is hydroxyl, methyl, fluorine, -CH2OH, -C(0)NH2, -CH2C(0)NH2, -CH2S(0)2NH2, -S(0)NH2, 1-imidazoly1 or two RX are taken together with adjacent carbon atoms to form a cyclobutyl, 1-__ tetrahydrofuranyl or 2-tetrahydrofuranyl, each of which is substituted with 0-3 occurrences of R.

(1r)p m O...OH/
nt W N
21. The compound of claim 18, wherein __ d'+' __ is 'Atm __ , H2N(0)C H2NO2S
SO2NH2 C(0)NH2 HOvC(0)NH2 < > 6 + + + + +
i-N
NHO 9 0 HO, OH F
--µ
14õO C-S 15 + , 0444,02NH2 b......./OH
N N N N N N N
d'iN + '+' +

Cilt H2 HO OH HO, õp02N H2 c3 0 0 IsQ-1 NH2 + low 4+0 ,OH 0 , or .
22. The compound of claim 16, wherein n is 1 and m is 1.
23. The compound of claim 22, wherein p is 0, 1, 2 or 3.
24. The compound of claim 23, wherein each IV is hydroxyl, cyano, oxo, halogen, C1-4 alkyl, Ci4 alkoxy, Ci4 haloalkyl, C3-7 cycloalkyl, 5-7 membered heteroaryl, -N(W)2, -T-RY, two W are taken together with adjacent carbon atoms to form a C3_7 cycloalkyl or 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of RY or two W
taken together can form a -C14 alkylene bridged ring substituted with 0-2 occurrences of RY.
25. The compound of claim 24, wherein each IV is hydroxyl, cyano, oxo, fluorine, methyl, methoxy, trifluoromethyl, difluoromethyl, chloromethyl, cyclopropyl, -NH2, 5 -oxazoly1,4-imidazolyl, -pyrazolyl, -NHC(0)0Me, -S(0)2Me, -NHC(0)Me, -NHC(0)-N(H) CH2CH20Me, -CH2OH, -NHS(0)2Me, -CO2H, -C(0)2Me, 1 -isopropanol, -S(0)2NH2, -C(0)N
H2, -S(0)2N(H)Me, -C(0)N(H)Me or two IV are taken together with adjacent carbon atoms to form a cyclopropyl, 1-tetrahydrofuranyl, 1-pyrrolidinyl or 2-pyrrolidinyl substituted with 0-3 occurrences of RY or two W taken together can form a methylene or ethylene bridged ring substituted with 0-2 occurrences of R.

X F4.. µ0 H
(Rx)pA) )m 0 0 N N
26. The compound of claim 24, wherein -4¨
is -4- -4-, , = H
Fn. µOH 0,0H OA 14 1114 N.0 M e H 0õ, CI' N%S02 M e 0 rf N N N N N
='+' -4^' Aim =+' 'Aim A
OH = NH2 NH2 Me0 NH OH
00,C(0)N H2 0.. 0.... cl OMe mum CHI Crel N N N N N N
pH 9H
, H
00.0 TOMe 0 N
y 0=CF3 0=CH F2 OH S%

N N N N N

F
, HOõ,cy_ 0,,,N H2 F....n,OH 14 NH2 H2NACt"
N N N N
F
0,0H crs02Me 00 N H2 (500H goµC(0)N H2 el N N N N N

µOH 0 N HSO2Me F3C OH F F
0/10H ()%
N N N N N N
-I-, , , ci =
I, 0#CO2Me 0,,CO2H 0.0 _ HON,30 % -OH (NIOH HO
N N N N N N
"4"' d`fm dim +' '+' =^1^' OH N r N H
cN),,,OH 0001 N N N N
"i^' =fti'v '+' + 4144 F C(0)NH2 .0C(0)NH2 Od=OH 00CN 00,S02N H2 (.5 00$02NH2 N N N N NI N
H0,40 HOn Me04%.0 ,OH 00S02NHMe 00S02Me N N N N N N
so2NH2 OH OH
(5 00C(0)N H2 0.0C(0)N H Me ,,,, 000H 000H (),OH
N N N N N N
H04,0.00H 0#C(0)N H2 ().,µC(0)N H2 c)o,C(0)N H2 N N N N
, 'AiA 4+1 444. 44N
(),,,S02NH2 mk, H
HO .--r) 0 r% 'N
0 L x--Nf.H i 0 'AiM jtiN 4 + or 414A
, =
27. The compound of claim 16, wherein n is 1 and m is 2; n is 2 and m is 1;
or n is 2 and m is 2.
28. The compound of claim 27, wherein p is 0, 1, 2 or 3.
29. The compound of claim 28, wherein RX is C14 alkyl, C14 alkenyl, cyano, hydroxy, halogen, oxo, -N(W)2, -T-RY or two W taken together can form a -0- or -Cl_4 alkylene bridged ring substituted with 0-2 occurrences of R.
30. The compound of claim 29, wherein Rx is hydroxy, cyano, oxo, fluorine, methyl, methenyl, -SO2NH2, -NHC(0)Me, -NHC(0)CF2H or two W taken together can form a -0- or methylene bridged ring substituted with 0-2 occurrences of R.
Ho, x 1 (1r)pl im 0 e
31. The compound of claim 29, wherein "4""' is HO .CN CN Ho, 5 OsiSO2NH2 N N N N N N
()....NHC(0)Me 0=NHC(0)CHF2 0=NH2 FIX¨) 0010H
N N N N N
''+' "I' , , , ,NH2 6_)I-1 OH pH F F pH
0 0.10H 0 (--),,--) 0 _______________ t) N N N N N N N
7_1(0 OH FFO FF d pH
______________________________________________________________________ no i a a LNJ ti:--)- -,LN0 (51 t:51 o + , ..vh. , ..+, , + , + , 41 al , 41N , "IN , -I-0 e N N
, or "I'v .
32. The compound of any of claims 1-15, wherein X is CH=CH.
33. The compound of claim 32, wherein n is 0 and m is 1 or n is 1 and m is 1.
34. The compound of claim 33, wherein p is 0 or 1.
35. The compound of claim 34, wherein each Rx is hydroxyl or oxo.
X .
(Rx) n,H
pl
36. The compound of claim 35, wherein ¨4¨ is 0,00H Cy 0 or
37. The compound of claim 1, wherein the compound is selected from one of the following compounds:
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidine-3-sulfonamide;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)pyrro1idine-3-carboxamide;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-yOpyrrolidine-2-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y0azetidine-2-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)piperidine-4-carboxamide;

(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114,3-alpyrimidin-4-yOpiperidine-3-sulfonamide;
2-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y0azetidin-3-ypacetamide;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3-d]pyrimidin-4-y1)-3-azabicyclo 113 .2.0]heptan-6-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidin-3-ol;
(3S,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3-alpyrimidin-4-y1)pyrradine-3,4-diol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)piperidin-3-01;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y1)piperidin-3-01;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidin-3-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido [4,3-alpyrimidin-7-y1)naphtha1en-2-o1;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido114,3-alpyrimidin-4-y1)pyrro1idin-3-01;
(1R,45)-2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y1)-azabicyclo[2.2.2loctan-6-ol;
3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-3-azabicydo 113 .2.1loctan-6-ol;

5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-45)-2-(hydroxymethypazetidin-1-y1)pyrido[4,3-d1pyrimidin-7-y1)naphtha1en-2-ol;
4-(4-((1S,5R)-3-Oxa-6-azabicyclo[3.2.01heptan-6-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo[3.2.01heptan-6-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-3-azabicyc1o[3.2.1loctan-6-ol (Isomer 1);
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyc1o[3.2.11octan-6-o1 (Isomer 2);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-5,5-dimethylpiperidin-3-ol;

(3R,65)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-01;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114,3 -d] pyrimidin-4-y1)-8-azabicyclo 113 .2 .1] octan-2-ol 2,2,2-trifluoroacetate;
(3R,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-01;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(hexahydro-5H-furo112,3-clpyrrol-5-y1)pyrido114,3-d1pyrimidin-7-y1)naphthalen-2-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yOpiperidin-3-ol (Isomer 1);
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido114,3-d1pyrimidin-4-yOpiperidin-3-ol (Isomer 2);
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido114,3-d1pyrimidin-4-y1)piperidin-3-ol (Isomer 1);
rel-5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yOpyrido[4,3-alpyrimidin-7-yl)naphthalen-2-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido114,3-cilpyrimidin-4-y1)-3-(fluoromethyl)piperidin-3-ol (Isomer 1);

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 - al pyrimidin-4-y1)-3-(fluoromethyl)piperidin-3-ol (Isomer 2);
(3R)-1-(7-(8-ethy1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-ol (Isomer 2);
(3R)-1-(7-(8-ethy1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-ol (Isomer 1);
(3R)-1-(7-(8-A11y1-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide;
4-(44(R)-3-Aminopiperidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
4-(44(S)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(44(R)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(3R,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-fluoropiperidin-3-01;
(R)-1-(7-(7,8-Difluoronaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(8-Ethyny1-7-fluoronaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-01;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-2-azabicydo[2.2.1lheptan-6-ol;

(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-l-y1)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
rel-(3aR,6a5)-5-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)hexahydropyrro1o[3,4-clpyrrol-1(2H)-one;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-re/-((3aR,7aS)-hexahydrofuro[3,2-clpyridin-5(4H)-yl)pyrido[4,3-c/Ipyrimidin-7-yl)naphthalen-2-ol;
rel-(3aR,7aR)-4-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y0octahydro-2H-pyrrolo[3,2-blpyridin-2-one;
rel-(3S,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidine-3-carboxamide;
3-Ethy1-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)piperidin-3-ol;

5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-4S)-3-(hydroxymethyl)-3-methylpiperidin-1-y1)pyrido[4,3-d]pyrimidin-7-y1)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-y1)pyrido[4,3-alpyrimidin-7-y1)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidine-3-carboxamide;
8-(7-(8-Ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3-alpyrimidin-4-y1)-2-methy1-8-azabicydo [3 .2.1loctan-2-ol;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3-cilpyrimidin-4-y1)-2-methy1-8-azabicyc1o[3.2.1loctan-2-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-6-methy1-2-azabicydo[2.2.1lheptan-6-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-y1)-2-azabicydo [2.2.1]heptan-6-one;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidin-3-ypacetamide;
14(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y1)piperidin-3-y1)-3-(2-methoxyethypthiourea;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-y1)-methylpiperidin-3-yl)methanesulfonamide;

N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-yl)acetamide;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y1)-methylpiperidin-3-yOcarbamate;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-yl)carbamate;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-2-methylazepan-1-y1)pyrido[4,3-4 pyrimidin-7-yl)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-methylazepan-1-y1)pyrido[4,3-4 pyrimidin-7-yl)naphthalen-2-ol;
(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azetidin-3-yl)methanesulfonamide;
.. 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-hydroxyazetidine-3-carboxamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-y1)pyrido[4,3 -d] pyrimidin-7-yl)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidine-4-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpyrrolidine-3-sulfonamide;
.. 1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yl)azetidine-3-sulfonamide;

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-yl)azetidine-3 -carboxamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-N-methylpiperidine-3 -carboxamide;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-yOpiperidine -3 -carboxamide ;
4-(4-(3 -(1H-Imidazol-1-yl)azetidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3 -methylazetidin-3 -01;
4-(4-(Azocan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d1pyrimidin-4-y0azepan-4-one ;
rac-(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5 -methylpiperidin-3 -01;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3 -azabicyclo [3 .2 .1] octan-8-ol ;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-8-methyl-3 -azabicyclo [3 .2.1] octan-8-ol;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3 -azabicyclo [4.1.0lheptan-l-ol;
rel-(3R,45)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-3,4-diol ;

rel-(3S,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-3,4-diol ;
rel-(3aR,7aR)-5 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y0octahydro-3H-pyrrolo [3,4-c] pyridin-3 -one ;
4444(5)-3 -Aminopiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
4-(4-(3 -Azabicyclo [3 .2.1] octan-3 -y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
4-(4-(3 -(1H-Imidazo1-4-yl)pipe ridin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -dlpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
4-(4-(3-(1H-Pyrazol-5-yl)piperidin-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -dlpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -(oxazol-5 -yl)pipe ridin-l-yl)pyrido [4,3 -d] pyrimidin-7-yOnaphthalen-2-o1;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-1,2,3,6-tetrahydropyridin-3 -ol ;
N-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpipe ridin-3-yl)methane sulfonamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-4-425,45)-4-fluoro-2-(hydroxymethyppyrrolidin-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
(3R,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-4-fluoropiperidin-3 -ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(R)-2-(hydroxymethyppyrrolidin-1-y1)pyrido [4,3 -d] pyrimidin-7-yl)naphthalen-2-ol ;

rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
(3S,45)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpyrrolidine-3,4-diol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-5,5 -difluoropiperidin-3 -ol ;
((S)-1-(7-(8-Ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-.. fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)pyrro1idin-2-yl)methane sulfonamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-5,5 -difluoroazepan-4-ol;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -azabicyclo l3 .2.1] octane -1-carboxamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-43aR,6aS)-tetrahydro-1H-furo [3,4-c] pyrrol-5(3H)-yl)pyrido [4,3-al pyrimidin-7-yl)naphthalen-2-ol ;
rac-(1S,55)-8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-8-azabicyc10 l3 .2.1] octane -2-carboxamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido [4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(S)-3 -(hydroxymethyl)pipe ridin-l-yl)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-ol ;
Methyl (R)-1-(7-(8-ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-.. fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yl)piperidine -3 -carboxylate ;

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y0azepan-3 -one ;
-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3 -(hydroxymethyl)piperidin-l-y1)pyrido [4,3 -d] pyrimidin-5 yl)naphthalen-2-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y0azepan-3 -01;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y0azepan-3 -01;
.. 4-(4-((R)-3-Aminoazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-ypazepan-3 -y1)-2,2-difluoroacetamide ;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-ypazepan-3 -ypacetamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-1,2,6,7-tetrahydro-3H-azepin-3-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-2,3,6,7-tetrahydro-1H-azepin-3 -ol;
1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylazepan-3 -o1 (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylazepan-3 -o1 (Isomer 2);

(R)-1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(( (2R,7aS)-2 -fluorotetrahydro- 1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpiperidine -3 -carboxylic acid;
-Ethy1-6-fluoro -4 -(8-fluoro -2 -(( (2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -5 yl)methoxy)-4 -(2,3 ,6,7-tetrahydro -1H-azepin-1 -yl)pyrido [4,3 -al pyrimidin-7-y1)naphthalen-2 -ol;
4 -(44(R) -5 -Amino -3,3 -difluoropipe ridin-1 -yl) -8-fluoro -2 -( ((2R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4 -y1)azepan-4 -o1;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-4-methy1azepan-4-o1;
4 -(4 - (4 -Aminoazepan- 1 -y1)-8-fluoro -2- (((2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1) -5 -ethy1-6-fluoronaphthalen-2 -ol ;
.. 5 -Ethy1-6-fluoro -4 -(8-fluoro -2 -(( (2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy) -4 -(4 -methyleneazepan-1 -yl)pyrido [4,3 -al pyrimidin-7-yOnaphthalen-2 -o1;
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 . 1] octane -6-carbonitrile (Isomer Mix 1);
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 . 1] octane -6-carbonitrile (Isomer Mix 2);
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 .2] nonane -6-carbonitrile;
(R)- 1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(((2R,7aS)-2 -fluorotetrahydro- 1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -al pyrimidin-4 -y1) -3 -(methyl-d3)piperidin-3-01;
(S) -1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(( (2R,7aS)-2 -fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4 -y1) -3 -(methyl-d3)piperidin-3-01;

-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -methoxy-3 -methylpipe ridin-l-yl)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-ol ;
4-(4-(4,4-Difluoroazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-5 .. 7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-5,5 -difluoroazepan-4-one ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cUpyrimidin-4-yl)piperidine-3 -carbonitrile ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3,3 -difluoropiperidin-4-one ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)pipe ridin-4-o1;

(3R,5S)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-5 -(trifluoromethyppiperidin-3 -01;
6-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-6-azabicydo [3 .2.1] octan-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -(trifluoromethyl)pipe ridin-3 -ol ;
3 -Cyclopropy1-1-(7-(8-ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpipe ridin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)azepane-3-su1fonamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -hydroxypipe ridine -3 -carboxamide;

4-(4-(34(Difluoromethyl)sulfonyl)piperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-5-methylpiperidine-3-carboxamide;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-yOpiperidine-3-sulfonamide;
4-(4-(Azepan-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(8-Chloro-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42S, 7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-ol bis(2,2,2-trifluoroacetate);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01; or (R)-1-(2-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoropyrido [4,3 -d] pyrimidin-4-y1)-3 -methylpiperidin-3 -ol .
38. The compound of claim 1, wherein the compound is selected from one of the following compounds:

(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidine-3-sulfonamide;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)pyrro1idine-3-carboxamide;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -alpyrimidin-4-y1)pyrradine-2-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y0azetidine-2-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)piperidine-4-carboxamide;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 sulfonamide;
2-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azetidin-3-yl)acetamide;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-azabicyclo[3.2.0lheptan-6-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-ol;
(3S,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)pyrradine-3,4-diol;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)piperidin-3-01;

(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-01;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3 -al pyrimidin-7-y1)naphthalen-2-o1;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yppyrrolidin-3-01;
(1R,45)-2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-azabicyclop.2.2loctan-6-ol;
3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicydo[3.2.1loctan-6-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(S)-2-(hydroxymethypazetidin-1-y1)pyrido[4,3 -al pyrimidin-7-y1)naphthalen-2-ol;
4-(4-((1S,5R)-3-Oxa-6-azabicyclo[3.2.01heptan-6-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo[3.2.01heptan-6-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);

3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyc1o[3.2.11octan-6-o1 (Isomer 2);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-.. fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(8-ethyny1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-5,5-dimethylpiperidin-3-01;
(3R,65)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-01;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-.. 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-8-azabicyclo[3.2.1loctan-2-ol 2,2,2-trifluoroacetate;
(3R,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-01;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(hexahydro-5H-furo[2,3-c1pyrro1-5-y1)pyrido[4,3-d1pyrimidin-7-y1)naphthalen-2-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yOpiperidin-3-ol (Isomer 1);

3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 2);
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
rel-5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7 aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-blpyridin-4(2H)-yOpyrido[4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide;
4-(44(R)-3-Aminopiperidin-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
.. 4-(44(S)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(44(R)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(3R,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-4-y1)-fluoropiperidin-3-01;
(R)-1-(7-(7,8-Difluoronaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)- 1-(7-(8-Ethyny1-7-fluoronaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-01;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-2-azabicyc1op.2.1lheptan-6-ol;
(R)- 1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;

(R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-l-y1)pyrido[4,3-c/Ipyrimidin-4-y1)-3-methylpiperidin-3-01;
rel-(3aR,6a5)-5-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-yphexahydropyrrolo[3,4-clpyrrol-1(2H)-one;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-re/-43aR,7aS)-hexahydrofuro[3,2-clpyridin-5(4H)-y1)pyrido[4,3-c/Ipyrimidin-7-y1)naphthalen-2-ol;
rel-(3aR,7aR)-4-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -c/Ipyrimidin-4-y0octahydro-2H-pyrrolo[3,2-b]pyridin-2-one;
rel-(3S,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidine-3-carboxamide;
3-Ethy1-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-yOpiperidin-3-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-4S)-3-(hydroxymethyl)-3-methylpiperidin-1-y1)pyrido[4,3-c/Ipyrimidin-7-y1)naphthalen-2-ol;

5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-4R)-3-(hydroxymethyl)-3-methylpiperidin-1-y1)pyrido[4,3-d]pyrimidin-7-y1)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidine-3-carboxamide;
8-(7-(8-Ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3-alpyrimidin-4-y1)-2-methy1-8-azabicydo [3 .2.1loctan-2-ol;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3-alpyrimidin-4-y1)-2-methy1-8-azabicydo [3 .2.1loctan-2-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3-alpyrimidin-4-y1)-6-methy1-2-azabicyc1o[2.2.1]heptan-6-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3-alpyrimidin-4-y1)-2-azabicydo [2.2.1]heptan-6-one;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidin-3-ypacetamide;
14(R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y1)piperidin-3-y1)-3-(2-methoxyethypthiourea;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-y1)methanesulfonamide;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-y1)-methylpiperidin-3-yl)acetamide;

Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-yOcarbamate;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidin-3-y1)carbamate;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y1)-N-methylpiperidine-3-sulfonamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(R)-2-methylazepan-1-y1)pyrido[4,3-alpyrimidin-7-yl)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(S)-2-methylazepan-1-y1)pyrido[4,3 -d] pyrimidin-7-yl)naphthalen-2-ol;
(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -cilpyrimidin-4-y0azetidin-3-yl)methanesulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-hydroxyazetidine-3-carboxamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-y1)pyrido[4,3 -cilpyrimidin-7-y1)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidine-4-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpyrrolidine-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-y0azetidine-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yl)azetidine-3-carboxamide;

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-N-methylpiperidine-3 -carboxamide ;
(S)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpiperidine -3 -carboxamide ;
4-(4-(3 -(1H-Imidazol-1-yl)azetidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -methylazetidin-3 -01;
4-(4-(Azocan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y0azepan-4-one ;
rac-(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5 -methylpiperidin-3 -01;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3 -azabicyclo [3 .2.1] octan-8-ol;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-8-methyl-3 -azabicyclo [3 .2.1] octan-8-ol;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3 -azabicyclo [4.1.0lheptan-l-ol;
rel-(3R,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-3,4-diol ;

rel-(3S,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-3,4-diol ;
rel-(3aR,7aR)-5 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y0octahydro-3H-pyrrolo [3,4-c] pyridin-3 -one ;
4444(5)-3 -Aminopiperidin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
4-(4-(3 -Azabicyclo [3 .2.1] octan-3 -y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
4-(4-(3 -(1H-Imidazo1-4-yl)pipe ridin-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -dlpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
4-(4-(3-(1H-Pyrazol-5-yl)piperidin-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -dlpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -(oxazol-5 -yl)pipe ridin-l-yl)pyrido [4,3 -d] pyrimidin-7-yOnaphthalen-2-o1;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-1,2,3,6-tetrahydropyridin-3 -ol ;
.. N-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpipe ridin-3-yl)methane sulfonamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-4-425,45)-4-fluoro-2-(hydroxymethyppyrrolidin-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
(3R,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-4-fluoropiperidin-3 -ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(R)-2-(hydroxymethyppyrrolidin-1-y1)pyrido [4,3 -d] pyrimidin-7-yl)naphthalen-2-ol ;

rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5-fluoropiperidin-3-ol;
(3S,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpyrrolidine-3,4-diol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-5,5-difluoropiperidin-3-ol;
((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)pyrro1idin-2-yl)methanesulfonamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-5,5-difluoroazepan-4-ol;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3-azabicyclo [3.2.1loctane-l-carboxamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-43aR,6aS)-tetrahydro-1H-furo[3,4-clpyrrol-5(3H)-y1)pyrido[4,3-alpyrimidin-7-y1)naphthalen-2-ol;
rac-(1S,55)-8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-8-azabicyc10 [3.2.1]octane-2-carboxamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(3-(2-hydroxypropan-2-y1)piperidin-1-y1)pyrido [4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(S)-3-(hydroxymethyl)piperidin-1-y1)pyrido [4,3 -alpyrimidin-7-yl)naphthalen-2-ol;
Methyl (R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-yOpiperidine-3-carboxylate;

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y0azepan-3 -one ;
-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-3 -(hydroxymethyl)piperidin-l-y1)pyrido [4,3 -d] pyrimidin-5 yl)naphthalen-2-ol;
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y0azepan-3 -01;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y0azepan-3 -01;
4-(4-((R)-3-Aminoazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-ypazepan-3 -y1)-2,2-difluoroacetamide ;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-ypazepan-3 -ypacetamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-1,2,6,7-tetrahydro-3H-azepin-3-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -al pyrimidin-4-y1)-2,3 ,6,7-tetrahydro-1H-azepin-3 -ol;
1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylazepan-3 -o1 (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -methylazepan-3 -o1 (Isomer 2);

(R)-1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(( (2R,7aS)-2 -fluorotetrahydro- 1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -al pyrimidin-4-yOpiperidine -3 -carboxylic acid;
-Ethy1-6-fluoro -4 -(8-fluoro -2 -(( (2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -5 yl)methoxy)-4 -(2,3 ,6,7-tetrahydro -1H-azepin-1 -yl)pyrido [4,3 -al pyrimidin-7-y1)naphthalen-2 -ol;
4 -(44(R) -5 -Amino -3 ,3 -difluoropipe ridin-1 -yl) -8-fluoro -2 -( ((2R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4 -y1)azepan-4 -o1;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -alpyrimidin-4-y1)-4-methy1azepan-4-o1;
4 -(4 - (4 -Aminoazepan- 1 -y1)-8-fluoro -2- (((2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1) -5 -ethy1-6-fluoronaphthalen-2 -ol ;
5 -Ethy1-6-fluoro -4 -(8-fluoro -2 -(( (2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy) -4 -(4 -methyleneazepan-1 -yl)pyrido [4,3 -al pyrimidin-7-yOnaphthalen-2 -o1;
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 . 2 . 1] octane -6-carbonitrile (Isomer Mix 1);
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 . 2 . 1] octane -6-carbonitrile (Isomer Mix 2);
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 .2] nonane -6-carbonitrile;
5 -Ethy1-6-fluoro -4 -(8-fluoro -2 -(( (2R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy) -4 -(3 -methoxy-3 -methylpipe ridin- 1-yl)pyrido [4,3 -al pyrimidin-7-y1)naphthalen-2-ol;
4 -(4 - (4,4 -Difluoroazepan- 1 -y1)-8-fluoro -2 -(((2R,7aS) -2 -fluorotetrahydro - 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1) -5 -ethy1-6-fluoronaphthalen-2 -ol ;

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -alpyrimidin-4-y1)-5,5 -difluoroazepan-4-one ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -cUpyrimidin-4-yl)piperidine-3 -carbonitrile ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-3,3 -difluoropiperidin-4-one ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -alpyrimidin-4-y1)pipe ridin-4-o1;
(3R,5S)-1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114,3 -cilpyrimidin-4-y1)-5 -(trifluoromethyppiperidin-3 -01;
6-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -alpyrimidin-4-y1)-6-azabicydo 113 .2 .1] octan-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -cilpyrimidin-4-y1)-3 -(trifluoromethyl)pipe ridin-3 -ol ;
3 -Cyclopropy1-1-(7-(8-ethyl-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido 114,3 -al pyrimidin-4-yOpipe ridin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido 114,3 -alpyrimidin-4-y1)azepane-3-su1fonamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)pyrido 114,3 -cilpyrimidin-4-y1)-3 -hydroxypipe ridine -3 -.. carboxamide;
44443 -((Difluoromethyl)sulfonyl)pipe ridin-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)pyrido 114,3 -cilpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)pyrido 114,3 -cilpyrimidin-4-y1)-5 -methylpiperidine -3 -carboxamide ;

(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidine-3-sulfonamide;
4-(4-(Azepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5,6-difluoronaphthalen-2-ol;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(8-Chloro-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-methylpiperidin-3-ol; or (R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)-8-methylpyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol.
39. The compound of claim 1, wherein the compound is selected from one of the following compounds:
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)pyrro1idine-3-carboxamide;
(S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-4-y1)pyrro1idine-2-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y0azetidine-2-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)piperidine-4-carboxamide;
2-(1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azetidin-3-ypacetamide;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-3 -azabicyclo [3 .2. 0] heptan-6-ol;

(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-yOpiperidin-3-ol;
(3S,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yOpyrrolidine-3,4-diol;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yl)piperidin-3-01;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-alpyrimidin-7-y1)naphtha1en-2-o1;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)pyrro1idin-3-01;
(1R,45)-2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-cilpyrimidin-4-y1)-2-azabicyc1o[2.2.21octan-6-o1;
3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-azabicyclo [3 .2.1loctan-6-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-4S)-2-(hydroxymethypazetidin-1-y1)pyrido [4,3-alpyrimidin-7-y1)naphtha1en-2-ol;
4-(4-((1S,5R)-3-Oxa-6-azabicyclo [3 .2.01heptan-6-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo [3 .2.01heptan-6-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;

3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
3-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-azabicyc1o[3.2.11octan-6-o1 (Isomer 2);
(1R,5R,6R)-3-(7-(8-ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
(1R,5R,6R)-3-(7-(3-chloro-2-cyclopropy1-5-hydroxypheny1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d1pyrimidin-4-y1)-azabicyclo[3.2.1loctan-6-ol (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-(methoxymethoxy)naphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-y1)-5,5-dimethylpiperidin-3-01;
(3R,65)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-01;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-8-azabicyclo[3.2.1loctan-2-ol 2,2,2-trifluoroacetate;
(3R,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-methylpiperidin-3-01;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(hexahydro-5H-furo[2,3-c1pyrro1-5-y1)pyrido[4,3-d1pyrimidin-7-y1)naphthalen-2-ol;
3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yl)piperidin-3-ol (Isomer 1);

3-(Difluoromethyl)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 2);
3-(Difluoromethyl)-1-(7-(8-ethyny1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yl)piperidin-3-ol (Isomer 1);
rel-5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7 aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-blpyridin-4(2H)-yOpyrido[4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-5,5-dimethylpiperidine-3-carboxamide;
4-(44(R)-3-Aminopiperidin-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
.. 4-(44(S)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
4-(44(R)-3-Amino-3-methylpiperidin-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-7-y1)-5-ethyl-6-fluoronaphthalen-2-ol;
(3R,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-4-y1)-fluoropiperidin-3-01;
(R)-1-(7-(7,8-Difluoronaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)- 1-(7-(8-Ethyny1-7-fluoronaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-methylpiperidin-3-01;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-2-azabicyc1op.2.1lheptan-6-ol;
(R)- 1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;

(R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(8-Ethy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-01;
(R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-l-y1)pyrido[4,3-c/Ipyrimidin-4-y1)-3-methylpiperidin-3-01;
rel-(3aR,6a5)-5-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-yphexahydropyrro1o[3,4-clpyrrol-1(2H)-one;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-re/-43aR,7a5)-hexahydrofuro[3,2-clpyridin-5(4H)-y1)pyrido[4,3-c/Ipyrimidin-7-y1)naphthalen-2-ol;
rel-(3aR,7aR)-4-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y0octahydro-2H-pyrrolo[3,2-blpyridin-2-one;
rel-(3S,6R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -c/Ipyrimidin-4-y1)-6-methylpiperidine-3-carboxamide;
3-Ethy1-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-c/Ipyrimidin-4-y1)piperidin-3-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-44(S)-3-(hydroxymethyl)-3-methylpiperidin-1-y1)pyrido[4,3-dlpyrimidin-7-y1)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-4R)-3-(hydroxymethyl)-3-methylpiperidin-1-y1)pyrido[4,3-c/Ipyrimidin-7-y1)naphthalen-2-ol;

1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-d]pyrimidin-4-y1)-3-methylpiperidine-3-carboxamide;
8-(7-(8-Ethy1-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-2-methy1-8-azabicyc10 [3 .2.1loctan-2-ol;
8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-dlpyrimidin-4-y1)-2-methyl-8-azabicyclo [3 .2.1loctan-2-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-6-methy1-2-azabicyc1o[2.2.1lheptan-6-ol;
2-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-4-y1)-2-azabicyc10 [2.2.1]heptan-6-one;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d] pyrimidin-4-y1)piperidin-3-ypacetamide;
1 -((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-yOpiperidin-3-y1)-3-(2-methoxyethypthiourea;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d] pyrimidin-4-y1)-3-methylpiperidin-3-yl)acetamide ;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-methylpiperidin-3-yOcarbamate;
Methyl ((R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidin-3-yl)carbamate;

5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-((R)-2-methylazepan-1-y1)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-((5)-2-methylazepan-1-yl)pyrido[4,3-4pyrimidin-7-yl)naphthalen-2-ol;
.. (1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y0azetidin-3-yl)methanesulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-3-hydroxyazetidine-3-carboxamide;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)-4-(3-(methylsulfonyl)piperidin-1-y1)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-alpyrimidin-4-yOpyrrolidine-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-ypazetidine-3-sulfonamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y0azetidine-3-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-N-methylpiperidine-3-carboxamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-3-methylazetidin-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y0azepan-4-one;
3-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3-alpyrimidin-4-y1)-3-azabicyclo[3.2.1]octan-8-ol;

3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-8-methyl-3 -azabicyclo [3 .2 .1] octan-8-ol;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -dlpyrimidin-4-y1)-3 -azabicyclo [4 . 1. 0lheptan-1-ol ;
rel-(3R,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-3,4-diol ;
rel-(3S,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-yOpiperidine-3,4-diol ;
rel-(3aR,7aR)-5-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4-y0octahydro-3H-pyrro10 [3,4-c] pyridin-3 -one ;
4-(44(S)-3 -Aminopiperidin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cil pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol;
4-(4-(3 -(1H-Imidazo1-4-yl)pipe ridin-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
4-(4-(3 -(1H-Pyrazol-5 -yl)pipe ridin-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2-ol ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3 -(oxazol-5 -yl)pipe ridin-l-yl)pyrido [4,3 -cil pyrimidin-7-yOnaphthalen-2-o1;
N-(1-(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cil pyrimidin-4-yOpipe ridin-3-yl)methane sulfonamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-4-425,45)-4-fluoro-2-(hydroxymethyppyrrolidin-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cilpyrimidin-7-yl)naphthalen-2-ol ;

(3R,4R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-4-fluoropiperidin-3 -ol ;
-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-5 yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido [4,3 -d]pyrimidin-7-yl)naphthalen-2-ol ;
rac-(3S,5R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4-y1)-5 -fluoropiperidin-3 -ol ;
(3S,45)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d1pyrimidin-4-yOpyrrolidine-3,4-diol ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrro1izin-7a(5H)-y1)methoxy)pyrido [4,3 -cilpyrimidin-4-y1)-5,5 -difluoropiperidin-3 -ol ;
((S)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-yOpyrrolidin-2-yl)methane sulfonamide ;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-5,5-difluoroazepan-4-ol;
3 -(7-(8-Ethy1-7-fluoro-3 -hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-3 -azabicyclo [3 .2.1] octane -1-carboxamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo [3,4-c] pyrrol-5 (3H)-yl)pyrido [4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
rac-(1S,55)-8-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d]pyrimidin-4-y1)-8-azabicydo [3 .2.1] octane -2-carboxamide ;
5 -Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido [4,3 -d]
pyrimidin-7-yl)naphthalen-2-ol ;

Methyl (R)-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidine-3-carboxylate;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-.. 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y0azepan-3-one;
4-(4-((R)-3-Aminoazepan-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-3-y1)-2,2-difluoroacetamide;
N-((R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -al pyrimidin-4-yl)azepan-3-ypacetamide;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-1,2,6,7-tetrahydro-3H-azepin-3-one;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-y1)-2,3,6,7-tetrahydro-1H-azepin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-o1 (Isomer 1);
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-y1)-3-methylazepan-3-o1 (Isomer 2);
(R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-y1)methoxy)pyrido[4,3 -d] pyrimidin-4-yOpiperidine-3-carboxylic acid;
5-Ethy1-6-fluoro-4-(8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3 -al pyrimidin-7-yl)naphthalen-2-ol;

4 -(4 - ((R) -5 -Amino -3,3 -difluoropipe ridin-1 -y1) -8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1)-5 -ethy1-6-fluoronaphthalen-2 -ol ;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-y1)azepan-4-o1;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-alpyrimidin-4-y1)-4-methy1azepan-4-o1;
4 -(4 - (4 -Aminoazepan-1 -y1)-8-fluoro -2 -(42R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1) -5 -ethy1-6-fluoronaphthalen-2 -ol ;
5 -Ethy1-6-fluoro -4 -(8-fluoro -2 -(42R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy) -4 -(4 -methyleneazepan-1 -yl)pyrido [4,3 -al pyrimidin-7-yOnaphthalen-2-o1;
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 . 1] octane -6-carbonitrile (Isomer Mix 1);
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -( ((2R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 . 1] octane -6-carbonitrile (Isomer Mix 2);
3 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1) -3 -azabicyclo I3 .2 .2] nonane -6-carbonitrile;
5 -Ethy1-6-fluoro -4 -(8-fluoro -2 -(42R,7aS) -2 -fluorotetrahydro -1H-pyrrolizin-7a(5H) -yl)methoxy)-4 -(3 -methoxy-3 -methylpipe ridin- 1-yl)pyrido [4,3 -al pyrimidin-7-y1)naphthalen-2-ol;
4 -(4 - (4,4 -Difluoroazepan-1 -y1)-8-fluoro -2 -(42R,7aS) -2 -fluorotetrahydro - 1H-pyrrolizin-7a(5H) -yl)methoxy)pyrido [4,3 -d] pyrimidin-7-y1) -5 -ethy1-6-fluoronaphthalen-2 -ol ;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -al pyrimidin-4 -y1)-5 ,5 -difluoroazepan-4-one ;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -(42R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3 -cUpyrimidin-4 -yl)piperidine -3 -carbonitrile ;
1 -(7- (8-Ethy1-7-fluoro -3 -hydroxynaphthalen-1 -y1)-8-fluoro -2 -( ((2R,7aS)-2 -fluorotetrahydro -1H-pyrrolizin-7a(5H)-y1)methoxy)pyrido [4,3 -d] pyrimidin-4 -y1)-3,3 -difluoropiperidin-4 -one ;

(3R,55)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-(trifluoromethyl)piperidin-3-01;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-cilpyrimidin-4-y1)-3-(trifluoromethyl)piperidin-3-ol;
3-Cyclopropy1-1-(7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -al pyrimidin-4-yOpiperidin-3-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-3-hydroxypiperidine-3-carboxamide;
4-(4-(34(Difluoromethyl)sulfonyl)piperidin-1-y1)-8-fluoro-2-(42R,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3 -d] pyrimidin-7-y1)-5-ethy1-6-fluoronaphthalen-2-ol;
1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-1-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-5-methylpiperidine-3-carboxamide;
(R)-1-(7-(8-Cyclopropy1-3-hydroxynaphthalen-l-y1)-8-fluoro-2-(42R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-dlpyrimidin-4-y1)-methylpiperidin-3-01;
(R)-1-(8-Chloro-7-(8-ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-4-y1)-methylpiperidin-3-ol; or (R)-1-(7-(8-Ethy1-7-fluoro-3-hydroxynaphthalen-l-y1)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(51-1)-yl)methoxy)-8-methylpyrido[4,3-dlpyrimidin-4-y1)-3-methylpiperidin-3-ol.
40. A pharmaceutical composition comprising the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable excipient.
41. A compound according to any one of claims 1-39, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition according to claim 40 for use as a medicament.
42. A compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 for use in treating cancer.
43. A compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 for use in treating cancer, wherein one or more cells express KRAS G12D mutant protein.
44. The compound or pharmaceutical composition for use of claims 42 or 43, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
45. A use of the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 in the preparation of a medicament for treating cancer.
46. A use of the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS
G12D mutant protein.
47. The use according to claim 45 or 46, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
48. A method of treating cancer in a subject in need thereof, the method comprising .. administering to the subject a therapeutically effective amount of the compound according to any one of to any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 40.
49. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 40, wherein one or more cells express KRAS
G12D mutant protein.
50. The method according to claim 48 or 49, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
51. The method according to claim 48 or 49, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
52. The method according to claim 51, wherein the cancer is non-small cell lung cancer.
53. The method according to claim 51, wherein the cancer is colorectal cancer.
54. The method according to claim 51, wherein the cancer is pancreatic cancer.
55. The method according to anyone of claims 48-54, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof
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