OA17165A

OA17165A - Alkoxy pyrazoles as soluble guanylate cyclase activators

Info

Publication number: OA17165A
Application number: OA1201500034
Authority: OA
Inventors: Jehrod Burnett Brenneman; John David Ginn; Michael D. Lowe; Christopher Ronald Sarko; Edward S. Tasber; Zhonghua Zhang
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2012-09-07
Filing date: 2013-09-03
Publication date: 2016-03-28

Abstract

The present invention relates to compounds of formula (I):

Description

FIELD OFTHE INVENTION

This invention relates to heterocyclic compounds which are useful as activators of soluble guanylate cyclase and are thus useful for treating a variety of diseases that are mediated or sustained by decrcased or diminished soluble guanylate cyclase actîvity, including cardiovascular diseases, rénal disease, diabètes, fibrotic disorders, urologie disorders, neurological disorders and inflammatory disorders. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

BACKGROUND

Soluble guanylate cyclase (sGC) is a receptor for nitric oxide (NO) which is found in the cytoplasm of many cell types. In humans, functional sGC is a heterodimer composed of either an alpha 1 or alpha 2 subunit combined with the beta l subunit which has a heme prosthetic group. Under non-pathophysiological conditions, NO binding to the heme of sGC activâtes the enzyme to catalyze the conversion of guanosine-5’-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is a second messenger which exerts effects by modulating cGMP dépendent protein kinase (PKG) isoforms, phosphodiesterases, and cGMP gated ion channels. In doing so, sGC has been demonstrated to modulate numerous pathways associated with diseases including arlerial hypertension, pulmonary hypertension, atherosclerosis, heart failure, liver cirrhosis, rénal fîbrosis, and erectile dysfunction (O. Evgenov et al., Nature

Reviews, 2006, 5, 755-768 and Y. Wang-Rosenke et al., Curr. Med. Chem., 2008,15, 13961406).

Under normal conditions, the iron in sGC exists in the ferrous state which is capable of binding to NO and carbon monoxide (CO). However, under conditions ofoxîdative stress which can occur in various diseases, published reports indicate that the heme iron becomes oxidized to the ferrie state which is incapable of being activated by NO or CO. The inability of NO to signal through sGC with an oxidized heme iron has been hypothesized to contribute to disease processes. Recently, two novel classes ofcompounds hâve been described which potentiate sGC activity in a heme dépendent (sGC stimulators) and heme independent (sGC activators) manner. The activity ofsGC stimulators synergizes with NO to increase cGMP production while sGC activators are only additive with NO to augment cGMP levels (O. Evgenov et al.. Nature Reviews, 2006, 5, 755-768). Both stimulators and activators of sGC hâve demonstrated benefit in animal models of disease. Activators of sGC provide the advantage of being able to preferentially target the diseased, non-functional form of the enzyme. sGC activators include BAY 58-2667 (cinaciguat) (J-P Stasch et al., Brit J. Pharmacol., 2002, 136, 773-783) and HMR1766 (ataciguat) (U. Schindler et al., 2006, Mol. Pharmacol., 69, 1260-1268).

NO has an important rôle in maintaining normal cellular and tissue function. However, adéquate signaling in lhe NO pathway can be disrupted at a number of steps. NO signaling can be impaired by reduced levels of nitric oxide synthase (NOS) enzymes, NOS activity, NO bioavailabiliiy, sGC levels, and sGC activity. sGC activators hâve the potential to bypass the functional impediment produced by ail of lhese impairments. Sînce sGC activation occurs downstream of NO synthesis or NO availability, these deficiencies will not impact the activity of sGC activators. As described above, lhe activity ofsGC in which function is disrupted by heme iron oxidation will be corrected by sGC activators. Thus, sGC activators hâve the potential to provide benefit in many diseases caused by defective signaling in the NO palhway.

Activation of sGC has the potential to provide therapeutic benefit for atherosclerosis and arteriosclerosis. Cinaciguat treatment has been demonstrated to prevent neointimal hyperplasia after endothélial dénudation by wire injury of the carotid artery in rats (K. Hirschberg et al., Cardiovasc. Res., 2010, 87, Suppl. 1, S100, Abstract 343). Ataciguat inhibited atherosclerotic plaque formation in ApoE-/- mice feed a high fat diet (M. van Eickels, B MC Pharmacology, 2007,7, Suppl. 1, S4). Decreased NO production in endothélial nitric oxide synthase (eNOS) deficienl mice increased vascular inflammation and insulin résistance in response to nutrient excess. In the same study, the phosphodiesterase 5 (PDE5) inhibitor sildenafiî reduced vascular inflammation and insulin résistance in mice fed a high-fat diet (N. Rizzo et al., Arterioscler. Thromb. Vase. Biol., 2010, 30,758-765). Lastly, after balloon-injury of rat carotid arteries in vivo, a sGC stimulator (YC-l) inhibited neotima formation (C. Wu, J. Pharmacol. Sci., 2004,94, 252-260

The complications of diabètes may be reduced by sGC activation. Glucose induced suppression 5 of glucagon release is lost in pancreatic islets that Jack PKG, thus suggesting a rôle of sGC mediated cGMP production in glucose régulation (V. Leiss et al., BMC Pharmacology, 2009,9, Suppl. I, P40).

It is well established clinically that élévation of cGMP by treatment with PDE5 inhibltors is efïicacious for the treatment of erectile dysfonction (ED). However, 30% of ED patients are résistant to PDE5 inhibitor treatment (S. Gur et al., Curr. Pharm. Des., 2010,16, I6l9- J633).

The sGC stimulator BAY-41-2272 is able to relax corpus cavemosum muscle in a sGC dépendent manner, thus suggesting that increased sGC activity could provide benefit in ED patients (C. Teixeira et al., J. Pharmacol. & Exp. Ther., 2007,322, 1093-1102). Furthermore, 15 sGC stimulalors and sGC activators used individually or either in combination with PDE5 inhibitor was able to treat ED in animal models (WO 10/081647).

There is evidence that sGC activation may be useful in preventing tissue fibrosis, including that of the lung, liver, and kidney. The processes ofépithélial to mesenchyal transition (EMT) and 20 fibroblast to myofîbroblast conversion are believed to contribute to tissue fibrosis. When either cincaciguat or BAY 41-2272 was combined with sildenafil, lung fibroblast to myofîbroblast conversion was inhibited (T. Dunkem et al., Eur. J. Pharm., 2007, 572, 12-22). NO is capable of inhibiting EMT of alveolar épithélial cells (S. Vyas-Read et al., Am. J. Physiol. Lung Cell Mol.

Physiol., 2007,293,12 J2-1221), suggesting that sGC activation is involved in this process. NO 25 has also been shown to inhibit glomerular TGF beta sîgnaling (E. Dreieicher et al., J. Am. Soc.

Nephrol., 2009,20, 1963-1974) which indicates that sGC activation may be able to inhibit glomerular sclerosis. In a pig sérum mode! and carbon tetrachloride mode! of liver fibrosis, an sGC activator (BAY 60-2260) was effective at inhibiting fibrosis (A. Knorr et al., ArzneimittelForschung, 2008,58,71-80).

Clinical studies hâve demonstrated eflîcacy using the sGC activator cinaciguat for the treatment of acute decompensated heart failure (H. Lapp et al., Circulation, 2009, 119, 2781-2788). This is consistent with résulte from a canine tachypacing-induced heart failure mode! in which acute intrevenous infusion of cinaciguat was able to produce cardiac unloading (G. Boerrigter et al., Hypertension, 2007,49, 1128-1133). In a rat myocardial infarction induced chrome heart failure mode!, HMR 1766 improved cardiac function and reduced cardiac fibrosis which was further potentiated by ramipril (F. Daniela, Circulation, 2009, 120, Suppl. 2, S852-S853).

Activators of sGC can be used to treat hypertension. This has been clearly demonstrated in clinical studies in which the dose of cinaciguat is titrated based on the magnitude of blood pressure réduction achieved (H. Lapp et al., Circulation, 2009,119, 2781-2788). Preclinical studies using cinaciguat had previously shown the ability of sGC activation to reduce blood pressure (J.-P. Stasch et al., 2006, J. Clin, lnvest., 116,2552-2561). Similar findings hâve been reported using the sGC activator HMR 1766 as well (U. Schindler et al., 2006, Mol. Pharmacol., 69, 1260-1268).

The activation of sGC has the potential to reduce inflammation by effects on the endothélium. BAY 41-2272 and a NO donor inhibited leukocyte rolling and adhesion in eNOS déficient mice. This was demonstrated to be mediated by down-regulation of expression of the adhesion molécule P-selectin (A. Ahluwalla et al., Proc. Natl. Acad. Sci. USA, 2004, 101, 1386-1391). Inhibitors of NOS and sGC were shown to increase endotoxin (LPS) induced ICAM expression on mesenteric microcirculation vessels. This was reduced by an NO donor in a cGMP dépendent manner. Treatment of mice with NOS or sGC inhibitors increased neutrophil migration, rolling, and adhesion induced by LPS or carrageenen (D. Dal Secco, Ni trie Oxide, 2006,15, 77-86). Activation of sGC has been shown to produce protection from ischemia-reperfusion injury using BAY 58-2667 in both in vivo and in an isolated heart model (T. Krieg et al., Eur. Heart J., 2009, 30, 1607-6013). Similar résulte were obtained using the same compound in a canine model of cardioplégie arrest and extracorporeal circulation (T. Radovits et al., Eur J. Cardiothorac. Surg.,

2010).

Some studies hâve indicated the potential of sGC activation to hâve antinociceptive efïects. In streptozotocin-induced diabètes models of nociception in mice (writhing assay) and rats (paw hyperalgesia), élévation of cGMP levels by administration of sildenafil blocked the pain response, which in tum was abrogated by a NOS or sGC înhibitor (C. Patil et al., Pharm., 2004,

72, 190-195). The sGC inhibitor l/Z-l,2,4.-oxadiazolo4,2-«.quinoxalin-l-one(ODQ) hasbeen demonstrated to block the antinociceptive efïects of various agents including meloxicam and diphenyl diselenide in a formalin induced pain model (P. Aguirre-Banuelos et al., Eur. J. Pharmacol., 2000,395,9-13 and L. Savegnago et al., J. Pharmacy Pharmacol., 2008,60, 16791686) and xylazine in a paw pressure model (T. Romero et al., Eur. J. Pharmacol., 2009,613,6410 67). Furthermore, ataciguat was antinociceptive in the carrageenan model of inflammatory triggered thermal hyperalgesia and the spared nerve injury model of neuropathie pain in mice (WO 09/043495).

Inhibiton of PDE9, a phosphodiesterase spécifie for cGMP expressed in the brain, has been t5 shown to improve long-term potentiation (F. van der Staay et al., Neuropharmacol. 2008,55,

908-918). In the central nervous System, sGC is the primary enzyme which catalyzes the formation of cGMP (K. Domek-Lopacinska et al., Mol. Neurobiol., 2010,41,129-137). Thus, sGC activation may be bénéficiai in treating Alzheimer's and Parkinson’s disease.

In a phase II clinical study, the sGC stimulator riociguat, was efficacous in treating chronic thromboembolie pulmonary hypertension and pulmonary arterial hypertension (II. Ghofrani et al„ Eur. Respir. J., 2010, 36, 792-799). These findings extend the preclinical studies in which BAY 41-2272 and cinaciguat reduced pulmonary hypertension in mouse (R. Dumitrascu et al.. Circulation, 2006, 113, 286-295) and lamb (O. Evgenov et al., 2007, Am. J. Respir. Crit. Care Med., 176, 1138-1145) models. Similar results were obtained using I1MR 1766 in a mouse model of pulmonary hypertension (N. Weissmann et al., 2009, Am. J. Physiol. Lung Cell. Mol. Physiol., 297, L658-665).

Activation ofsGC has the potential to treat chronic kidney disease. Both BAY 58-2667 and

HMR 1766 improved rénal fonction and structure in a rat subtotal nephrectomy model of kidney 30 disease (P. Kalk et al., 2006, Brit. J. Pharmacol., 148,853-859 and K. Benz et al., 2007, Kidney

Blood Press. Res., 30, 224-233). Improved kidney fonction and survival was provided by BAY

58-2667 treatment in hypertensive renin transgenic rats (TG(mRen2)27 rats) treated with a NOS inhibitor (J.-P. Stasch et a!., 2006, J. Clin. Invest., 116, 2552-2561). BAY 41-2272 treatment preserved kidney function and structure in a chronic model of kidney disease in rats induced by uninephrectomy and anti-thy 1 antibody treatment (Y. Wang et al., 2005, Kidney Intl., 68,47-61). Diseases caused by excessive blood clotting may be treated with sGC activators. Activation of sGC using BAY 58-2667 was capable of inhibiting platelet aggregation induced by various stimuli ex vivo. Additionally, this compound inhibited thrombus formation in vivo in mîce and protonged bleeding time (J.-P. Stasch et at., 2002, Brit. J. Pharmacol., 136,773-783). tn another study using HMR 1766, in vivo platelet activation was inhibited in streptozotocin treated rats (A. Schafer et a!., 2006, Arterioscler. Thromb. Vase. Biol., 2006,26,2813-2818).

sGC activation may also be bénéficiai in the treatment of urologie disorders (WO/08138483). This is supported by clinical studies using the PDE5 inhibitor vardenafi! (C. Stief et al., 2008, Eur. Urol., 53, 1236-1244). The soluble guanylate cyclase stimulator BAY 41-8543 was able to inhibit prostatic, urethra, and bladder smooth muscle cell prolifération using patient samples (B. Fibbi et al., 2010, J. Sex. Med., 7,59-69), thus providing further evidence supporting the utility of treating urologie disorders with sGC activators.

The above studies provide evidence for the use of sGC activators to treat cardiovascular diseases including hypertension, atherosclerosis, peripheral artery disease, restenosis, stroke, heart failure, coronary vasospasm, cérébral vasospasm, ischemia/reperfusion injury, thromboembolie pulmonary hypertension, pulmonary arterial hypertension, stable and unstable angina, thromboembolie disorders. Additionally, sGC activators hâve the potentiel to treat rénal disease, diabètes, fibrotic disorders including those of the liver, kidney and lungs, urologie disorders including overactive bladder, benign prostatic hyperplasie, and erectile dysfunction, and neurological disorders including Alzheimer’s disease, Parkinson’s disease, as well as neuropathie pain. Treatment with sGC activators may also provide benefits in infiammatory disorders such as psoriasis, multiple sclerosis, arthritis, asthma, and chronic obstructive pulmonary disease.

BRIEF SUMMARY OFTHE INVENTION

The présent invention provides novel compounds which activate or potentiate sGC and are thus useful for treating a variety of diseases and disorders that can be alleviated by sGC activation or potentiation including cardîovascular, inflammatory and rénal diseases. This invention a!so relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates usefut in these processes.

In a further aspect, the présent invention provides activa tors of soluble guanylate cyclase having solubility properties consistent with acceptable pharmacokinetic properties. As is known in the art, poorly soluble compounds may suffer from poor human exposure. The compounds of the présent invention would be expected to hâve exposure properties consistent with being a suitable drug.

In a further aspect, the présent invention provides compounds with metabolic stability properties consistent with acceptable pharmacokinetic properties. As is known in the art, compounds having poor metabolic stability may not readily achieve désirable therapeutic levels. The compounds of the présent invention would be expected to hâve metabolic stability properties consistent with being a suitable drug.

DETAILEDDESCRIPTIONOFTHE INVENTION

In an embodiment, there are provided compounds of the formula I

wherein:

A is a 5-7 membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, wherein one carbon of said heterocyclyl group is optionally substituted with one or two groups seiected from Cj.jalkyl and oxo ;

R* is Cm alkyl optionally substituted with a methoxy group;

R² is seiected from H, F, Cl, C1.3alkyl.-CN, -OMe and -CF3;

R³ is seiected from H and -CH3;

R⁴ is seiected from H, F, -CH3 and -OMe;

R^s is seiected from H, Cl, -CHj, -CH2CH3, -CF3, F, and -OMe;

R⁶ is bonded to lhe nitrogen on A and is seiected from H, Ci^alkyl, -(CH₂)_nC3^cycloalkyl, C(O)Ci^alkyl, -(CH₂)_n heterocyclyl, -(CH₂)_n aryl -(CH₂)n heteroaryl, -SO₂aryl, SO₂C|.6alkyl wherein said Ci^alkyl, -(CH₂)_n heterocyclyl, -(CH₂)_n cycloalkyl, -(CH₂)_n aryl and -(CH₂)_n heteroaryl are optionally substituted with one to four groups independently selected from Cj. jalkyl, halogen, C|.₃alkoxy, -CFj, -OH, oxo, -(CH₂)|.jO(CH₂)₂.jOH, and-SO₂CH_J;

R⁷ is selected from H, -CHj, -CH₂CHj, -CFj, F, and -ON;

n is 0, t or 2 or a sait thereof.

In another embodiment, there are provided compounds as described in the embodiment above, wherein:

A is a 5-7 membered saturated heterocyclyl group containing one nitrogen, wherein one carbon of said heterocyclyl group is optionally substituted with one or two C i .jalkyl groups;

R* is Ci.jalkyt;

R² is selected from H, F, Cl, C|.jalkyl, -CN, -OMe and -CFj;

R³ is selected from H and -CH3;

R⁴ is selected from H and F;

R^s is selected from H, Cl and -CHj;

R⁶ is bonded to the nitrogen on A and is selected from H, C|_*alkyl, -(CH₂)_nCj^cycloalkyl, 25 C(O)C|₄alkyt₍ -(CH₂)_n heterocyclyl, -(CH₂)_n aryl and -(CH₂)_n heteroaryl, wherein said C₍. ₆alkyl, -(CH₂)_n heterocyclyl, -(CH₂)_n cycloalkyl, -(CH₂)_n aryl and -(CH₂)_n heteroaryl are optionally substituted with one to four groups independently selected from Ci.jalkyl, halogen, Ci.jalkoxy, -CFj, -OH and -SO₂CHj_;

R⁷ is H;

and n is 0,1 or 2; or a sait thereof.

In another embodiment, there are provided compounds as described in any of the embodiments above, wherein:

R¹ is methyl, ethyl or isopropyl; and

or a sait thereof.

In another embodiment there are provided compounds as described in any of the embodimenls above, wherein:

R² is selected from -CHj, F, Cl, and -CFj; and

R⁶ is selected from H, Ci^alkyl, -(CH₂)_nC3^cycloalkyl, -C(O)Ci^alkyl and -(CH₂)_n heterocyclyl, wherein said Ci^alkyl, -(CH₂)_n cycloalkyl and -(CH₂)_n heterocyclyl are optionally substituted with one to four groups independently selected from Ci.jalkyl, halogen, Cualkoxy, -CF3, -OH and -SO₂CH₃;

or a sait thereof.

In another embodiment there are provided compounds as described in any of the embodiments above, wherein said heterocyclyl referred to in R⁶ is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabîcyclo[3.2.0]heptanyl, [l,4]dioxanyl, 8-oxabicyclo[3.2.l]octanyl, Ioxaspiro[4.5]decanyl and pyrrolidin-2-one;

said heteroaryl referred to in R⁶ is selected from imidazolyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl and 4,5,6,7-tetrahydrobenzothiazolyl;

and said aryl referred to in R⁶ is phenyl;

or a sait thereof.

In another embodiment there are provided compounds as described in any of the embodiments above, wherein:

R⁶ is -(CH₂)n heterocyclyl, wherein said heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [l,4]dioxanyl, 8oxabicyclo[3.2.l]octanyl and I-oxaspiro[4.5]decanyl;

or a sait thereof.

R²is-CH₃;

R³ is H;

R⁴isHor-CH₃;

R^s is H, or-CHj;

R⁷ is in the position para to R^s and is H, -CHj or-CHîCHj;

or a sait thereof.

the group

or a sait thereof.

R³ is H; and

R⁴ is H;

or a sait thereof.

Table 1 shows représentative compounds of the invention which can be made by the general synthetic schemes, the examples, and known methods in the art.

Table 1

Cpd No.	Structure
1	δ ⁿ’n^K9
3	_Vo«
5	A cù. A F

Cpd No.	Structure
2	A ^N-nA F
4	N. >-n CA WXT
6	A Ai O-J

t3

J °- “8 b_a	t?	x /Λ- O o- '«0	O _o- O“ J
00	O	CN
X fVü 8 h	x fA-e* 9 o— / \ “ ^8	J θ' 7=< 7 U. U.	O o- O^- ^{J 0} 8 Λ
Γ-	o	-	m

τ	rf-\		Z	ÿ-\-	z ΓΧ-		Z	zy
θ ο-	\=/		9 o-	/⁼\	9 o—		θ O-	\=z
	ο °	y	z—	(\ °~y	°Vji		1 ^z—	o °~	b
		-ρ	k'* * ^•z		Li*- · \ f Z \=Z Q—		^z	x=/ Q—
		Q b		0		0-Z b			b,
Ό	00	O n	<N <N
Ζ θ ο-	/“V		T 9 O-	/“A_	z ry ? θ' >=<		z F\ ? θ' 7=\
Ζ~* k'* * ^•ζ		b	cr\if\ Γ z^z”	X—/ θ—\	^Z \=/ Q-		cpyp, z^•z	<3 °	_/y
		Q		Q		'—Z			Y-z
		Ôo		b					Y
	«Ί			r-	O
								n

oo

	LA		LA		U		•U
	LP				O		—J
q ο		°ς o		A ’ Q		°Q ο
Q.		X	<fYA o )=z	Q	o PaY	q-	o qq^o
Ή —	Q ? η	Q-	0\ o V_? ' ^z		-o s
	LA		LA		LA		-U
	-U		bJ		o		00
0		Q		p		Q n
	/Ύ*Γί	Q.	o	R	Ο-2^ηί o 2=z	q
η-	O )=Z fY° Ό ^s	n-	)=\ ° θ V? ¹	Q-	O A ⁵		_o-o y-z -0 s
			Π

Ο CN

δ Ο”	? Q^-	* ! €V- o o-/	δ oJ Q
ARp-h	•Wb	“W-b	° c^z<5 ^c	1
Q -0	Q -0	Q è		Q λχ£_ο/
3	Ό Ό	00 *o	O Γ
z $ u. O o- \=Ç	δ oJ Q-	F	S J {	-\_
			°r>-o ^Z \=/
o	Q	v>
X- z 0				d
ΓΌ		r-	σ'
Ό	Ό	Ό	*O

CM

CM CM

κ> <-Α

ο	Ό Ό	Ό	Ό Μι
? -Ο *	q x Q²X >=< -° ο Ο ^χ	Ο Ρ' K Q’Xo -Ο r° s	0~' -ο C °
ο Κ)	ο ο	Ο 00	Ό Ο
% ^-ο W ry° -Ο ®	>=< -° ο —ά λ X	Q Κ,σ-Χ. Ο ¹	-η Γ KΛ>Χο -Ο γ° *

j A	? o- OcA-X 5=\ L/A-/		δ o-	? J Q^- a
O 7—\	A 0	_)	2 y.
104	106	108	110
? Q· ²⁼\ °·		δ X		δ o- Q	O-	5 A ÇX
t ^#Z_\__y		°W °	b	Q A? _	b	A
	A		%		A	%
103	105	107	601

δ J _Q“ h	? J Q^- 0	s A Q- ^Ό_!	3 O	j S^~ ό
	'T	Ό		00
	β*

	j A Q^-	s A Q
	«ϊ^’νΛ f=\ °\	^^*<7 z=< °
	R	kTV
Q o	Q O		Q b
	m	v->		r-

		*

	J Q“ b	? AQ~ b>	δ o- Q
	O CM	CM CM	fH
j a_q~	« J Q-	5 <s Q~	j cA_Q~

b	<t>	b	b
	O\	rM	CM

CM

? Q^-	? _OJ Q^-	5 p- Q~	δ Q”
	οΑΧ f=\ °-\		<ΑγΧ 7=\ °~\
^w -Q	-Ώ	h
%	Q O	O Ό	Q b
O	00	O	<N
	ΓΊ	en	en

i J _Q~	δ o- _Q^	i J Q“
		Άο
Q a	w Λ O O	Q b	o O=
νΊ	r-	θ'
ΓΊ	<N	CM	<*ΐ
			“

? X 0·		s X Q-		s Q-	δ o- Q-
J '^c		cf^· J z-=Z			r^A». —-Z Φ=\ °A
	^b	^/A_? _	b	noo
	b		Q	Q 1	Q
	b		b	xr°°	b
		o		OQ	o
r*T		m		m
		··
J ^5-	r~	I »<P		s X Q-	J O-
	o-V	-A ^z x ⁽	5—\		⁰Tz-7 ù °b—x
	-Q	Vv	-h	-b	ηζ,^ΞΧ
	O		o	o	c>
	'—Z b		'—Z b	'—Z h	X o o
m		<n		r-	o
m		m		m	m
··		·*

f —θ '—z > 0^0 VJ	j A_Q b	ι δ Q^- d	c/Ό _θ b
n TT	TT TT	Ό 'T	00
b	Vjjj ό	δ o- Q ô	d“
TT	m	't	t-~ 't

1 d Q-		? χ Q·				I /	S-< =/ ο—
Ζ=/ ο—		Χ/Ό _	-Η		Va	°ζ>^	_/ _	κ
P w _	Ο		Γ$	ζ _Γ	Η			Η
	Q 6		> Ο		Q Ρ			V/ Ρ ζ
150	152	154	156
		j/p		υ 5	)— °~\	JX	yy Ζ=/ C	τ.
Ζ=/ C	τ.		^ι—\.	°Q-O	-Η	Γ 2— L- /		-Π
Q-Q	-Ρ	ζτΟ	-Q		ο			ο
	Q Ρ		Q Ρ		V/ d			b
149	</Ί	*η	155

? <	δ o- O~	J J J^^-	s Z Q~
		V 'r^* X / X \	4. / -w /
Q_b·		-0
O 0	Q.» c< / Ό	0	Q h
oo	O	<N
	O	Ό	O

? Q^-	8 J Q-	s A Q-	J J £5“
-Jn. / y—ί Ο—X	/ 7—1	/ 1—( &““\	f—\ °^\
/ \ \	4·^” X f \ x
L/-U Zy^&	L/-W	U/AJ Q_	-g
Q 0	Q b	Q 0	>d
Γ	O		m
		O	O

j _ Rz		X	$-4		X	yy·		HO-	Vf^-
		z=< o-			z=Z o		CF^X-*^
	A	ΊΓ z— L·- / ^Z	Vf _	b	I z-H L&- / '	Vf .		Γ z— ^-z	°Έ
				Q			Q O o \—/		b₂>
	b			s t \_r				3
Ό			oo			o			<N
Ό			Ό			r-			t-
s J Çf-		I	yy		1	Υύ 7—/ 1
ô-		1 Z- L·*. /	C-f	%	Tl· ^z~ L·^, / ^z	Vy	Έ-
				Q~			Q
				b			b
v>			r-			O


	δ _OJ	? Q~	? ο- 0“
		Λ \ °~~\
	Yrf *>y	V-U _λΛ	-b-
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In one embodîment, the invention relates to any of the compounds depicted in Table 1 above and the pharmaceuticaily acceptable salts thereof.

In another embodîment the invention relates to the group of compounds depicted in Table 1 consisting of compound number 1,2,3,4,5,7,8,9,12, 15, 16,18,21,27,28,30,31,35,36,39, 41,42,44,45,46,47,48, 57,59, 62,68, 77,78,79, 80, 82,83,84, 85, 86,88,92,93, and 94 and the pharmaceuticaily acceptable salts thereof.

In another embodîment the invention relates to the group of compounds depicted in Table 1 consisting o f compound number 95,97,100,101,102,103, 104, 105, 106,107, 108, 109, 110, 111,112, 113,114,115,116, 117,118,119,120,121,122,123,124,125,126,127,128, 129, 130,131, 132, 136,137,139,140, 141,142,145,146, 152,153,154,155,157,158, 159,161, 162,163, 164,165,166,167, 169,170,171,172,173, 174, 175,176,177,178,179,180, 181, 184,185, 186,187, 188,189, 191,193, 194,195,196, 197,198,199,201,202,203,204,205, 206,207,208,210,211,212,213,214,215,216,220,222,223,224,225,227,229,230,231, 232,233,234, 235,236,237, 238,239,240,241,242,243,244,246,247,248,249,250,251, 252,253,254, 255,256,257 and the pharmaceuticaily acceptable salts thereof.

Unless specificaliy indicated, throughout the spécification and the appended daims, a given chemical formula or name shall encompass tautomers and ail stéréo, optical and geometricai isomers (e.g. enantiomers, diastereomers, E/Z isomers ,etc.) and racemates thereof as weil as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceuticaily acceptable salts thereof and solvatés thereof such as for instance hydrates including solvatés of the free compounds or solvatés of a sait of the compound.

Some of the compounds of formula (I) can exist in more than one tautomeric form. The invention includes methods for using ail such tautomers.

The invention includes pharmaceutically acceptable dérivatives of compounds of formula (I). A pharmaceutically acceptable dérivative refers to any pharmaceutically acceptable sait or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active métabolite or 5 pharmacologically active residue thereof. A pharmacologically active métabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized dérivative compounds of the formula (I).

As used herein, pharmaceutically acceptable salts refer to dérivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salis of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include acétates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methylbromides, methylnitrates, methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenyl acétates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stéarates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnésium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the présent invention (e.g. trifluoro acetate salts) also comprise a part ofthe invention.

In addition, within the scope of the invention is use of prodrugs of compounds of the formula (I). Prodrugs include those compounds that, upon simple chemical transformation, are modified to to produce compounds ofthe invention. Simple chemical transformations include hydrolysis, oxidation and réduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.

The compounds of the invention are only those which are contemplated to be ‘chemically stable’ as will be appreciated by those skilled in the art. For example, a compound which would hâve a ‘dangling valency’, or a ‘carbanion’ are not compounds contemplated by the inventive methods disclosed herein.

For ail compounds disclosed herein above in this application, in the event the nomenclature is in conflict with the structure, it shall be understood that the compound is defîned by the structure.

Ail terms as used herein in this spécification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, “Ci4alkyl”is a saturated aliphatic hydrocarbon monovalent radical containing 1 -4 carbons such as methyl, ethyl, n-propyl, 1 methylethyl (isopropyl), n-butyl or r-butyl; “Cm alkoxy” is a Cm alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy. Ail alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched, cyclized or uncyclized where structurally possible and unless otherwise specified. Other more spécifie définitions are as follows:

The term “C₁^_I-alkyl”, wherein n is an integer from 2 to n, either alone or in combination with another radical dénotés an acyclic, saturated, branched or Iinear hydrocarbon radical with 1 to n C atoms. For example the term C_t._s-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2CH₂-, HiC-CHfCHj)-, H3C-CH2-CH2-CH1-, HjC-Cfb-CHiCHj)-, H3C-CH(CH3)-CH₂-, H₃C. C(CH3)₂-, H3C-CH2-CH1-CH2-CH2-, H3C-CH₂-CH2-CH(CH3)-, HjC-CH2-CH(CH3)-CH2-, h₃cCH(CH₃)-CH2-CH2-, H3C-CH₂-C(CH3)2-, H3C-C(CH₃)2-CH2-, H₃C-CH(CH3)-CH(CH3)- and HjC-CH2-CH(CH2CH3)-.

The term C|^-alkylene wherein n is an integer 1 to n, either alone or in combination with another radical, dénotés an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term Cn-alkylene includes -(CH2)-, -(CH2-CH2)’, (CHfCHj))-, -(CH2-CH2-CH2)-, -(C(CHj)₂)-, -(CH(CH₂CHj))-, -(CH(CHj)-CH2)-, -(CH₂CH(CHj))-, -(CH2-CH2-CH2-CH2)’, -(CH2-CH₂-CH(CHj))-, -(CH(CHj)-CH₂-CH2>, -(CH₂CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C (CHih-CHj)-, -(CH(CH3)-CH(CHj))-, -(CH₂CH(CH2CH3))-, -(CH(CH2CHj)-CH2)-, -(CH(CH2CH₂CH3))-, -(CHCHfCHih)- andC(CH3)(CH₂CH3)-.

The term “Cj-n-cycloalkyl”, wherein n is an integer 4 to n, either alone or in combination with another radical dénotés a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3.7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “heteroatom” as used herein shall be understood to mean atoms other than carbon such as O, N, S and P.

In ail alkyl groups or carbon chains one or more carbon atoms can be optionally replaced by heteroatoms: O, S or N, it shall be understood that if N is not substituted then it is NH, it shall also be understood that the heteroatoms may replace either terminal carbon atoms or internai carbon atoms within a branched or unbranched carbon chain. Such groups can be substituted as herein above described by groups such as oxo to resuit in définitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.

The terni “aryl as used herein, either atone or in combination with another radical, dénotés a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

The term heteroaryi means an aromatic 5 to 6-membered monocyclic heteroaryi or an aromatic 7 to 11-membered heteroaryi bicyclic ring where at least one of the rings is aromatic, wherein the heteroaryi ring contains 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5 to 6-membered monocyclic heteroaryi rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, letrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7 to 11membered heteroaryi bicyclic heteroaryi rings include benzimidazolyl, quinolinyl, dihydro-2/7quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl and benzo thiazolyl.

The term heterocyclyl means a stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical. The 5 to 11-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be either saturated or partially unsaturated. Non-limiting examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l.l-dioxo-ΐλ⁶thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of nonaromatic 6 to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to 11-membered bridged bicyclic radicals include 2-azabicyclo[2.2.1]heptanyl, 3azabicyclo[3.1 .OJhexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to 11-membered spirocyclic heterocyclic radicals include 7-aza50 spiro[3,3 ]heptanyl, 7-spiro[3,4]octanyl, and 7-aza-spiro[3,4]octanyl. The term “heterocyclyl” or is intended to include ail the possible isomeric forms.

The term “halogen as used in the présent spécification shall be understood to mean bromine, chlorine, fluorine or iodine. The définitions “halogenated”, “partially or fuily halogenated;

partially or fully fluorïnated; “substituted by one or more halogen atoms, includes for example, mono, di or tri halo dérivatives on one or more carbon atoms. For alkyl, a non-limiting example would be -CH2CHF2, -CF3 etc.

to Each alkyl, cycloalkyt, heterocycle, aryl or heteroaryl, or the analogs thereof, described herein shall be understood to be optionally partially or fully halogenated.

As used herein, “nitrogen or N and “sulfur” or S includes any oxidized form of nitrogen and sulfur and the quatemized form of any basic nitrogen.. For example, for an -S-C|^ alkyl radical, 15 unless otherwise specified, this shall be understood to include -S(O)-C|^ alkyl and -S(O)i-C|^ alkyl, likewise, -S-R, may be represented as phenyl-S(O)_m- when R, is phenyl and where m is 0, 1 or 2.

GENERAL SYNTHET1C METHODS

The compounds of the invention may be prepared by the general methods and examples presented below and methods known to those of ordinary skill in the art. Optimum reaction conditions and reaction times may vary dépending on the particular reactants used. Unless otherwise specified, solvents, températures, pressures, and other reaction conditions may be 25 readily selected by one of ordinary skill in the art. Spécifie procedures are provided in the

Synthetic Examples section. Intermediates used in the synthèses below are either commercially available or easily prepared by methods known to those skilled in the art. Reaction progress may be monitored by conventional methods such as thtn layer chromatography (TLC) or high pressure lîquid chromatography-mass spec (HPLC-MS). Intermediates and products may be 30 purified by methods known in the art, including column chromatography, HPLC, préparative TLC or recrystallization.

The methods described below and in the Synthetic Examples section may be used to préparé the compounds of formula I.

Compounds of formula I may be prepared as described in Scheme 1

Scheme 1

As illustrated above, diester II (R = Me or Et) and hydrazine III are reiluxed in a suitable solvent such as éthanol with a suitable base such as potassium carbonate (K₂COj) yielding hydroxy pyrazole IV. Compound IV is alkylated, for example by using trimethylsilyldiazomethane in some cases or R¹! and a suitable base such as césium carbonate (Cs2CO2). Altematively, Mitsunobu conditions are employed with éthanol to yield the desired alkoxy pyrazole chloropyridine V (R¹ = Et). Chloropyridine, V, is coupled with boron species, VI, in the presence of a palladium catalyst such as tetrakis(triphenyl)phosphine (0) and a suitable base such as Na2COi in aqueous 1,2-DME (1,2-dimethoxyethane) under microwave irradiation at 120 to °C to provide VII. Alkylation ofthe phénol intermediate, VII with alkyl bromide VIII, where X

- Cl, 1 or Br using a base such as césium carbonate (Cs₂COj) in a solvent such as acetone at about 50 °C. Subséquent deprotection ofthe t-Boc group with a suitable acid such as trilluoroacetic acid (TFA) provides compound IX. Reductive amination of amine, IX, with the desired ketone or aldéhyde using an appropriate hydride source such as NaBHjCN in a solvent t5 such as MeOH containing an organic acid such as AcOH at about 50 °C, followed by in situ hydrolysis with a base such as aqueous LiOH affords the desired compound of formula I.

Altematively, alkylations of amine, IX with akyl halides in the presence of a suitable base such as césium carbonate (Cs₂COj) orM/V-diisopropylethylamine (DtPEA) in a solvent such as MeCN (acetonitrile) followed by hydrolysis of the ester provides the desired compound of 20 formula I.

UPLC/MS Methods

Rétention times (RT) reported for compounds in the Synthetic Examples section are obtained by 25 UPLC/MS using one of the following methods:

For each of the methods, the following are identical:

UPLC/MS System components- Acquity UPLC with PDA, SQ and ELS detectors.

PDA conditions-Détection: 2I0to400nm. Sampling rate: 20pts/sec. Filter response: fast.

ELSD conditions-Gain: 1000. Sampling rate: 20pts/sec. Drifi tube temp: 55° C. Nebulizer mode: cooling. Gas pressure: 41 psi.

MS conditions- Instrument: Acquity SQD with ESCi source. lonization mode: ESI+/-. Capillary voltage: 3.5 kV. Cône voltage: 5 V. Extractor: 1.3 V. Source temp: 150° C. Desolvation temp: 350° C. Desolvation gas: 800 L/hr. Cône gas: 50 L/hr.

Conditions spécifie to each method are as follows

Method Al

Column- Waters BEH C18,2.1x50mm, 1.7 um particle diameter.

Description and Gradient: Medium polar fast gradient method. ESI+/- ion mode 80-1000Da.

Gradient: 90%A to 100%B in 1.19 minutes hold at 100%B to 1.70 minutes. Flow rate 0.8mL/min. A=(95%Water 5% Acetonitrile 0.05% Formic Acid) B=(Acetonitrile 0.05% Formic Acid).

Sample Injection Volume: I uL

Method A2

Column- Waters BEH Cl 8,2.1x50mm, 1.7 um particle diameter.

Description and Gradient: Medium polar long gradient method. ESÏ+/- ion mode 80-IOOODa.

Gradient: 90%A to 100%B in 4.45 minutes hold at 100%B to 4.58 minutes. Flow rate 0.8mL/min. A=(95%Water 5%Acetonitrile 0.05% Formic Acid) B=(Acetonitrile 0.05% Formic Acid).

Sample Injection Volume: 2 uL

Method B1

Column- CSH 2.1x50mm Cl 8,1.7 um particle diameter.

Gradient: 90%A to 100%B in 1.19 minutes hold at I00%B to 1.70 minutes. Flow rate 0.8mL/min. A=(95%Water 5% Acetonitrile 0.05% Formic Acid) B=(Acetonitrile 0.05% Formic Acid).

Sample Injection Volume: I uL

Method B2

Column- CSH 2.1 x50mm C18, 1.7 um particle diameter.

Description and Gradient: Medium polar long gradient method. ES 1+7- ion mode 80-1000Da.

Gradient: 90%A to IOO%B in 4.45 minutes hold at IOO%B to 4.58 minutes. Flow rate 0.8mL/min. A=(95%Water 5%Acetonitrile 0,05% Formic Acid) B=(Acetonitrile 0.05% Formic Acid).

Sample Injection Volume: 2 uL

Method AI is used for ail of the compounds except for compounds noted for which Method A2, Method BI, or Method B2 isused.

SYNTHETIC EXAMPLES

Final compounds are designated by compound numbers correspondîng to the compound numbers in Table 1. Intermediates are given hyphenated numbers correspondîng to the figures and numbers shown in the scheme for each example.

Example 1: Préparation of Intermediate l-[6-(2-hydroxy-3-methyl-phenyl)-py rldin-2-yl]-5-lsopropoxy-lH-pyrazole-4*carboxyllc acid ethyl ester (1-6)

1-3 1-4

To a round bottom flask containing EtOH (200 mL), K₂COj (20.05 g, 55.720 mmol), and 11(10.00 g, 69.65 mmol) is added 1-2 (13.95 mL, 69.65 mmol). The resulting mixture is refluxed for 3 h. The réaction is cooled and the solid is collected by filtration. This solid is removed from the fritted funnel and is placed into a beaker to which is added 250 mL of 1.0 N HCl (excessive bubbling). The solution is confirmed to be acidic (pH 2) and then dichloromethane (500 mL) is added. The mixture is stirred until ail solid is dissolved. The organic layer is collected, dried over MgSO₄, and concentrated to afford 1-3 (17.18 g) as an off-white solid.

to A reaction mixture of 1-3 (0.50 g, 1.87 mmol), 2-iodopropane (372.92 pL, 3.74 mmol), Cs₂CO₃(0.91 g, 2.80 mmol) in DMA (9.0 mL) is heated at 150 °C in a microwave reactor for 10 min. The mixture is added to water and is extracted with EtOAc (2x). The organic layers are washed with water, brine, dried over MgSO₄, and concentrated. The crude is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptane to yield the desired product 1-4 (0.41 g).

To a microwave vial is added 1-4 (1.00 g, 3.29 mmol), 1-5 (0.69 g, 4.52 mmol), Pd(PPh₃)₄ (0.37 g, 0.32 mmol), DME (15.0 mL), and 2.0 M Na₂CO₃ (4.36 mL, 8.72 mmol). The reaction mixture is heated in microwave reactor at 120°C for 20 min. The réaction is extracted with dichloromethane (2x), washed with water, brine, dried over Na₂SO₄, and concentrated. The resulting matériel is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptane to yield the desired product 1-6 (0.41 g).

Example 2: Préparation of intermedlate l-[6-(2-hydroxy-3-methyI-phenyl)-py rldin-2-yl|-5-methoxy-lll-pyrazole-4-carboxylic acid ethyl ester (2-8)

Intermediate 1-3 (7.00 g, 26.15 mmol) is dissolved in 1:1 mixture EtOAc/MeOH (50.0 mL). 2.0 M TMSCHN2 in hexanes (42.70 mL, 85.40 mmol) is then added slowly via a syringe. The reaction is stirred for 3 h and is quenched by the addition of acetic acid (4.0 mL). The mixture is stirred for 10 min and then concentrated. The resulting residue is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptane to yield the desired product 2-7 (4.460 g) as an off-white solid.

To a microwave vial is added 2-7 ( 1.50 g, 5.33 mmol), 1-5 (0.890 g, 5.86 mmol), Pd(PPhj)₄(0.62 g, 0.532 mmol), DME (12.0 mL), and 2.0 M Na₂CO₃ (6.922 mL, 13.85 mmol). The reaction mixture is heated in a microwave reaclor at 120 °C for 20 min. The reaction is extracted with dichloromethane (2x), washed with water, brine, dried over MgSO₄, and concentrated. The resulting material is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptane to yield the desired product 2-8 (1.17 g).

The following intermediates are synthesized in a similar fashion from the appropriate reagents:

Example 3: Préparation of intermediate 5-ethoxy-l-[6-(2-hydroxy-3-methyi-p henyi)-pyridin-2-yi]-lH-pyrazoie-4-carboxyiic acid ethyl ester (3-15)

l-(6-Ch!oro-pyridin-2-y!)-5-hydroxy-lH-pyrazo!e-4-carboxyIic acid ethy! ester, 1-3, (3.50 g, 13.08 mmol) is dissolved in THF (90.0 mL). Triphenylphosphine (3.77 g, 14.383 mmol) and éthanol (1.14 mL, 19.614 mmol) are added and the reaction is cooled to 0 °C. The resulting suspension is slowly dissolved at 0 °C as diisopropyl azodicarboxylate (3.09 mL, 15.691 mmol) is added dropwise over 10 min. The reaction mixture is allowed to warm to ambient température and is stirred for 16 h. The reaction is concentrated in vacuo and the residue is dissolved in a minimal amount of dichloromethane and subjected to silica gel chromatography using a gradient of 3-50% EtOAc in heptane to yield the desired product 3-14 (3.33 g).

To a microwave vial is added 3-14 (250.0 mg, 0.85 mmol), 1-5 (134.9 mg, 0.89 mmol), Pd(PPhj)₄ (60.05 mg, 0.05 mmol), DME (5.0 mL), and 2.0 M Na₂COj (1.06 mL, 2.1 ! mmol). The reaction mixture is heated in a microwave reactor at 120 °C for 20 min. The reaction is extracted with dichloromethane (2x), washed with water, brine, dried over MgSO₄, and concentrated. The resulting material is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptane to yield the desired product, 3-15 (227.0 mg).

The following intermediate is synthesized in a similar fashion from the appropriate reagents:

k, Q-°	Lçt Q-	l 7 f~\— o \ >=<	a p-	A Q-
° Χ>α3 ¹	° yAJ ^x	U_h-^zA7	° C/AJ ^x	° C/AJ ¹
	r-	00	©V	e
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«A	1 i*ï	«A	<A	1 <*ï

Example 4: Préparation of intermediate 6-bromomethy!-3,4-dihydro-lIl-isoquino!ine-2carboxylic acid tert-butyl ester (4-19)

Compound 4-17 (12.50 g, 45.08 mmol) is dissolved in dry THF (125.0 mL) under nitrogen at 25 °C. Borane THF complex (99.17 mL, 99.17 mmol) is added via syringe and the mixture is stirred at 25 °C for 16 h. Water (10.0 mL) is slowly added and then 2.0 M Na₂COj (15.0 mL).

This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected. The organics are rinsed with 1.0 M HCl, dried over MgSO<, and concentrated in vacuo to afford an oil. The oil is purified by silica gel chromatography using a gradient of 1080% EtOAc in heptane to yield the desired product, 4-18 (11.78 g), as a white solid.

To a solution of alcohol, 4-18, (9.50 g, 36.08 mmol) and N.N-diisopropylethylamine (9.43 mL,

54.11 mmol) in dichloromethane (200.0 mL) is added triphenylphosphine dibromide (23.79 g,

54.11 mmol) at 0 °C. The reaction is stirred for 1 h and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using a gradient of 7-60% EtOAc in heptanes to yield the desired product, 4-19 (8.74 g), as a white solid.

The following intermediates are synthesized in similar fashion from the appropriate reagents:

4-20	•'Όδψ Ύ
4-21
4-22	-XQ A⁰ O

4-23	XQ
4-24	xoç

Example 5: Préparation of Intermediate 6-bromomethyl-5-methyi-3,4-dlhydro-lIIl$oquinollne-2-carboxyllc acid tert-butyl ester (5-34)

5-23 5-24

SOClj

5-27

6-28

5-25

A solution ofacid 5-23 (350.0 g, 2.10 mol) in THF (1.4 L) is added to a slurry of LAH (95.9 g, 1.40 mol) in THF (2.5 L) at 0 °C. The mixture is stirred at room température for 0.5 h, then heated to reflux for 1 h. The mixture is then cooled to 0 °C, and slowly quenched by the addition of saturated aqueous ammonium chloride solution. A large excess of solid Na₂SO4 and EtOAc are added, then the solids are collected by filtration. The filtrate is concentrated in vacuo to afford crude 5-24 (350.0 g) which is used directly in the next step.

To a solution of compound 5-24 (294.0 g, 1.90 mol) in dichloromethane (2.2 L) at -10 °C is added thionyl chloride (SOCI₂) (460.0 g, 3.90 mol). Then the reaction mixture is heated to reflux for 1 h, followed by concentration in vacuo to provide crude 5-25 (298.0 g) which is used directly in the next step.

A mixture of compound 5-25 (298.0 g, 1.8 mol) and NaCN (154.5 g, 2.1 mol) in DMF (1.2 L) is stirred at room température for 12 h, then extracted with EtOAc and H₂O. The organic layer is dried over Na₂SO₄, fîltered, and concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether:EtOAc = 50:1) to deliver intermdiate 5-26 (230.0 g).

A mixture of compound 5-26 (180.0 g, 1.10 mol), Raney Ni (40.0 g) and aqueous ammonia (250.0 mL) in MeOH ( 1.0 L) is stirred under H₂ (50 psi) at room température for 5 h. The mixture is then fîltered and concentrated to give compound 5-27 (165.0 g) that is used directly in the next step.

A solution of compound 5-27 (165.0 g, 1.0 mol) and aqueous formaldéhyde (HCHO) (37 wt%,

30 g, 1.0 mol) in formic acid (HCO₂H) (1.5 L) is stirred at 50 °C ovemight, then the solvent is removed in vacuo to afford compound 5-28 (150.0 g) which is used directly in lhe next step.

Compound 5-28 (150.0 g, 847 mmol) is suspended in aqueous HBr (48%, 1.0 L), then heated to

100 °C ovemight. Removal of the solvent in vacuo provides compound 5-29 (195.0 g) which is 30 used directly in the next step.

To a solution of compound 5-29 (195.0 g, 799 mmol) in THF (1.0 L) and H2O (1.0 L) is added EtjN (242.0 g, 2.4 mol) and BOC2O (174.0 g, 799 mmol). The resulting mixture is stirred at room température ovemight, then extracted with EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by silica gel chromatography (using 10:1 petroleum ether:EtOAc) to provide compound 5-30 (100.0 g).

To a solution of compound 5-30 (100.0 g, 380 mmol) and EtjN (76.8 g, 760 mmol) in dichlorométhane (1.5 L) cooled to 0°C is added triflic anhydride (TfiO) (107.0 g, 380 mmol) via 10 addition funnel. Upon complété addition of Tf₃O, the solution is warmed to room température for 5 h. The reaction mixture is then treated with H2O and dichlorométhane, and the organic phase is separated, washed with brine, dried over Na2SO«, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound 5-31 (105.0 g).

Compound 5-31 (50.0 g, 127 mmol) is combined with palladium (II) acetate (PdfOAch) (5.0 g), dppp (5.0 g) and EljN (25.7 g, 254 mmol) in EtOH (1.0 L), then stirred at 80 °C ovemight under CO at a pressure of 4 MPa. The mixture is cooled to room température, then the solids are removed by filtration. The nitrate is concentrated in vacuo, and the remaining residue is purified 20 by silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound 5-32 (25.0 g).

To a solution of LAH (12.5 g, 330 mmol) in THF (400 mL) cooled to -30°C is added dropwise a solution of compound 5-32 (35.0 g, 110 mmol) in THF (400 mL) over 30 min. Aller addition, 25 the reaction mixture is stirred at 0°C for 30 min, then treated with H2O and dichlorométhane.

The organic phase is separated, washed with brine, dried over Na2SÛ4, filtered, and concentrated in vacuo. The crude product is purified by silica gel chromatographyl (using 10:1 petroleum ether:EtOAc) to provide the desired intermediate 5-33 (21.1 g).

To a solution of alcohol, 5-33, (6.00 g, 21.63 mmol) and N,N-diisopropylethylamine (5.65 mL,

32.45 mmol) in dichlorométhane (200.0 mL) is added triphenylphosphine dibromide (14.27 g,

32.45 mmol) at 0 °C. The reaction is stirred for 1 h and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using a gradient of 7-60% EtOAc in heptanes to yield the desired product, 5-34 (6.60 g), as a white solid.

Example 6: Préparation of intermediate 6-Bromomethyl-5-chloro-3,4-dlhydro-llIisoquinollne-2-carboxylic acid tert-butyl ester (6-39)

6-37 δ*³⁸

To a solution of N,N,N’-trimethyl-ethane-l,2-diamine (45.0 g, 442.0 mmol) in THF (500 mL) is added a solution of n-BuLi ( 177.0 mL, 442 mmol) at -40 °C under Nî. The mixture is stirred at 40 °C for 30 min. After the mixture is cooled to-70 °C, compound 6-35 (50.0 g, 368 mmol) in THF (250 mL) is added to the reaction mixture. The mixture is allowed to warm to 0 °C and stirred for 30 min. Then the réaction mixture is cooled to-78 °C and n-BuLi (177.0 mL, 442 mmol) is added. The mixture is allowed to warm to 10 °C and is cooled to -30 °C before it is added to a solution of C2CI6 (287.0 g, 1.1 mol) in THF (600 mL). The mixture is stirred 2 h at room température. The reaction mixture is poured into 1000 mL of 10% HCl solution and extracted with EtOAc. The organic layers are washed with brine, dried over NaîSCh, concentrated, and purified by silica gel chromatography to give compound 6-36 (36.7 g).

To a solution of compound 6-36 (105.0 g, 615 mmol) in HOAc (700 mL) is added NH4OAC (47.4 g, 615 mmol) at room température under N₂. To this reaction mixture is added MeNO₂(188.0 g, 3.08 mol) and the mixture is warmed to 40°C for 12 h and then is stirred at 85°C for 6 h. TLC showed the reaction is completed. The mixture is quenched with H2O and is extracted with dichioromethane. The organic layers are washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography to give compound 6-37 (97.5 g).

To a solution of compound 6-37 (48.0 g, 225 mmol) in THF (900 mL) is added LAH (34.1 g, 5 899 mol) at -20 °C. The mixture is stirred at room température for 5 h and 50 °C for 30 min.

The mixture is quenched with H2O and is extracted with dichioromethane. The organic layers are washed with brine, dried over NaîSO, and concentrated to give compound 6-38 (28.0 g) which is used directly in the next step.

The following compound is prepared from intermediate 6-38 according to the procedure descnbed in Example 5:

6-39

Ύ

Example 7: Préparation of 5-Isopropoxy-l-(6-{3-methyi-2-|2-(tetrahydro-pyran-4-yl)15 1,2,3,4 -tetrahydro-isoquinolln-6-yimethoxy|-phenyl}-pyridin-2-yl)-lII-pyrazole-4carboxylic acid (1)

Intermediate 1-6 (373.0 mg, 0.88 mmol), bromide 4-19 (287.1 mg, 0.88 mmol) and Cs₂COj (573.5 mg, 1.76 mmol) are combined in acetone ( 11.0 mL) and heated to 50 °C for 5 h. The reaction mixture is extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated. The resulting material is purified by silica gel chromatography (using a gradient of

5-100% EtOAc/heptane) to provide the desired intermediate, 7-40 (502.0 mg).

The carbamate, 7-40, (496.0 mg, 0.79 mmol) is dissolved in dichloromethane (4.0 mL) and treated with TFA (1.0 mL) at room température. After 1 h the mixture is neutralized with saturated NaHCOj solution and the layers are separated with a hydrophobie frit. The organic filtrate is concentrated to afford 7-41 (375.0 mg).

Amine 7-41 (98.0 mg, 0.19 mmol) is combined with 4 A molecular sieves (30 mg), tetrahydropyran 4-one (28 pL, 0.28 mmol), AcOH (20 pL), and Na(CN)BHj (24 mg, 0.38 mmol) in MeOH (4 mL). The mixture is stirred at room température for 30 min, and then heated to 50 °C for 12 h. The mixture is diluted with THF (1.0 mL) and water (1 mL). To this is added LiOH (42.8 mg, 1.86 mmol) and the reaction is heated to 50 °C for 2 h. It is then concentrated under N₂, triturated with 1:1 MeOH/DMSO, filtered through a 0.45 micron syringe filter, and the filtrate is purified by gradient elution (10-100% MeCN/water + 0.1% HCO₂H) on a Gilson RPHPLC. Concentrated in vacuo to afford title compound 1 (64.0 mg). MS, electrospray, m/z ·»

583.3 [M+H], RT 0.71 min.

Example 7A: Procedure is équivalent to Example 7, however during reductive amination step Na(OAc)îBH in dichloromethane is substituted for NaCNBHj/AcOH/MeOH.

The following compounds from Table I are prepared according to the procedure described in Example 7, using the appropriate starting materials and purification conditions:

Compound 2: MS, electrospray, m/z = 617.3 [M+H], RT 0.79 min;

Compound 37: MS, electrospray, m/z = 541.3 [M+H], RT 0.75 min; Compound 38: MS, electrospray, m/z = 571.4 [M+H], RT 0.76 min; Compound 39: MS, electrospray, m/z = 555.3 [M+H], RT 0.73 min; Compound 40: MS, electrospray, m/z = 583.3 [M+H], RT 0.73 min; Compound 41: MS, electrospray, m/z = 569.3 [M+H], RT 0.73 min;

Compound 42: MS, electrospray, m/z = 583.3 [M+H], RT 0.75 min;

Compound 109: MS, electrospray, m/z « 569.4 [M+H], RT 0.77 min;

Resolution: ChiralPak AD-H Prep 40% i-Propanol(l% ÎPrNH₂):CO₂ @ 80 ml/min., 100 bar, 25°C

Compound 111 : MS, electrospray, m/z = 569.4 [M+H], RT 0.77 min;

Resolution: ChiralPak AD-H Prep 40% i-Propanol(l% iPrNH₂):CO₂ @ 80 ml/min., 100 bar, 25°C

Compound 113: MS, electrospray, m/z = 583.3 [M+H], RT 0.75 min;

Resolution: Lux Cellulose 2 Prep 60% MeOH(l% iPrNH₂):CO₂ @ 55 ml/min., 100 bar, 25°C

Compound 115: MS, electrospray, m/z = 583.3 [M+H], RT 0.75 min;

Compound 144: MS, electrospray, m/z - 569.4 [M+H], RT 0.77 min.

The following compounds from Table 1 are prepared according to the procedure described in

Example 7, using phénol, 1-6, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 43: MS, electrospray, m/z = 555.4 [M+H], RT 0.77 min;

Compound 44: MS, electrospray, m/z = 585.4 [M+H], RT 0.80 min;

Compound 45: MS, electrospray, m/z = 569.3 [M+H], RT 0.75 min;

Compound 46: MS, electrospray, m/z = 597.4 [M+H], RT 0.76 min;

Compound 47: MS, electrospray, m/z = 583.3 [M+H], RT 0.76 min;

Compound 48: MS, electrospray, m/z = 597.4 [M+H], RT 0.77 min;

Compound 104: MS, electrospray, m/z ® 597.5 [M+H], RT 0.80 min;

Compound 116: MS, electrospray, m/z = 597.4 [M+H], RT 0.77 min;

Resolution: Lux Cellulose 2 Prep 65% MeOH(l% iPrNH₂):CO₂ @ 60 ml/min., 125 bar, 25°C

Compound 117: MS, electrospray, m/z « 597.4 [M+H], RT 0.77 min;

Compound 122: MS, electrospray, m/z = 581.5 [M+H], RT 0.72 min;

Resolution: RegisPack Prep 15% 1PA(1% diethylamine): CO₂ @ 12 ml/min., 120 bar, 40°C

Compound 123: MS, electrospray, m/z = 581.5 [M+H], RT 0.72 min.

Resolution: RegisPack Prep 15% IPA(1% diethylamine): CO₂ @ 12 ml/min., 120 bar, 40°C

The following compounds from Table 1 are prepared according to the procedure described in Example 7, using phénol, 2-8, bromide, 4-19, and other appropriate starting matériels and purification conditions:

Compound 3: MS, electrospray, m/z = 555.3 (M+H], RT 0.64 min;

Compound 5: MS, electrospray, m/z = 587.2 [M-H], RT 0.78 min;

Compound 8: MS, electrospray, m/z = 527.2 [M+H], RT 0.69 min;

Compound 12: MS, electrospray, m/z = 555.3 [M+H], RT 0.68 min;

Compound 13: MS, electrospray, m/z = 513.2 [M+H], RT 0.70 min;

Compound 14: MS, electrospray, m/z = 541.3 [M+H], RT 0.77 min;

Compound 15: MS, electrospray, m/z = 541.2 [M+H], RT 0.68 min;

Compound 23: MS, electrospray, m/z = 543.3 [M+H], RT 0.70 min;

Compound 24: MS, electrospray, m/z = 525.2 [M+H], RT 0.72 min;

Compound 25: MS, electrospray, m/z = 539.3 [M+H], RT 0.75 min;

Compound 61: MS, electrospray, m/z = 583.3 [M+H], RT 0.72 min;

Compound 62: MS, electrospray, m/z = 583.4 [M+H], RT 0.72 min;

Compound 73: MS, electrospray, m/z = 611.4 [M+H], RT 0.75 min;

Compound 75: MS, electrospray, m/z = 593.4 [M-H], RT 0.72 min;

Compound 81: MS, electrospray, m/z = 585.1 [M+H], Method A2, RT 1.42 min;

Compound 86: MS, electrospray, m/z = 569.4 [M+H], RT 0.78 min;

Compound 87: MS, electrospray, m/z = 581.4 [M+H], RT 0.80 min;

Compound 90: MS, electrospray, m/z = 583.4 [M+H], RT 0.80 min;

Compound 91: MS, electrospray, m/z = 583.4 [M+H], RT 0.83 min;

Compound 92: MS, electrospray, m/z = 571.4 [M+H], RT 0.79 min;

Compound 102: MS, electrospray, m/z = 609.4 [M+H], RT 0.83 min;

Compound 103: MS, electrospray, m/z = 609.4 [M+H], RT 0.89 min;

Compound 188: MS, electrospray, m/z = 555.3 [M+H], RT 0.58 min;

Compound 192: MS, electrospray, m/z = 555.3 [M+H], RT 0.58 min.

The following compounds from Table l are prepared according to the procedure described in Example 7, using phénol, 2-8, bromide, 4-20, and other appropriate starting materials and purification conditions:

Compound 10; MS, electrospray, m/z « 555.2 [M+H], RT 0.82 min;

Compound 89: MS, electrospray, m/z = 583.4 [M+H], Method A2, RT 1.80 min.

The following compounds from Table 1 are prepared according to the procedure described in 10 Example 7a, using phénol, 2-8, bromide, 4-20, and other appropriate starting materials and purification conditions:

Compound 217: MS, electrospray, m/z = 569.3 [M+H], 1.45 min (method B2);

Compound 218: MS, electrospray, m/z = 583.3 [M+H], 1.52 min (method B2);

Compound 219: MS, electrospray, m/z = 599.3 [M+H], 1.46 min (method B2);

The following compounds from Table 1 are prepared according to the procedure described in Example 7, using phénol, 2-8, bromide, 4-21, and other appropriate starting materials and purification conditions:

Compound 59: MS, electrospray, m/z = 541.3 [M+H], RT 0.66 min;

Compound 85: MS, electrospray, m/z = 513.2 [M+H], RT 0.71 min.

The following compound from Table 1 is prepared according to the procedure described in 25 Example 7, using phénol, 2-8, bromide, 4-22, and other appropriate starting materials and purification conditions:

Compound 100: MS, electrospray, m/z = 569.4 [M+H], RT 0.77 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7, using phénol, 2-8, bromide, 4-23, and other appropriate starting matériels and purification conditions:

Compound 130: MS, electrospray, m/z = 571.4 [M+H], RT 0.69 min (Method B1 );

The following compounds from Table 1 are prepared according to the procedure described in Example 7, using phénol, 2-8, bromide, 5-34, and other appropriate starting matériels and purification conditions:

Compound 16: MS, electrospray, m/z = 541.2 [M+H], RT 0.70 min;

Compound 27: MS, electrospray, m/z = 569.3 [M+H], RT 0.70 min;

Compound 28: MS, electrospray, m/z = 569.3 [M+H], RT 0.70 min;

Compound 30: MS, electrospray, m/z = 555.3 [M+H], RT 0.77 min;

Compound 31: MS, electrospray, m/z = 555.3 [M+H], RT 0.70 min.

The following compounds from Table 1 are prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 105: MS, electrospray, m/z = 555.4 [M+H], RT 0.72 min

Resolution: Chirapak AD-H, 20x250mm; MeOH to 30 mg/mL, 35% EtOH (1% DEA) in heptane over 18 min, ambient temp. and collection at 290nm;

Compound 106: MS, electrospray, m/z = 555.4 [M+H], RT 0.72 min

Compound 127: MS, electrospray, m/z = 569.4 [M+H], RT 0.76 min;

Compound 139: MS, electrospray, m/z = 585.4 [M+H], RT 0.74 min

Resolution: Chiracel OD-H, 20x250mm; 10%MeOH in CO₂ at 55.5g/min over 28 min, 140 Bar, 40°C and collection at 254 nm;

Compound 140: MS, electrospray, m/z = 569.4 [M+H], RT 0.74 min

Resolution: Chiracel OD-H, 20x250mm; 10%MeOH in CO₂ at 58g/min over 30 min, 120 Bar, 40°C and collection at 254 nm;

Compound 141: MS, electrospray, m/z = 569.4 [M+H], RT 0.74 min

Resolution: Chiracel OD-H, 20x250mm; 10%MeOH in CO₂ at 58g/min over 30 min, 120 Bar, 5 40°C and collection at 254 nm;

Compound 142: MS, electrospray, m/z = 585.4 [M+H], RT 0.74 min

Compound 191: MS, electrospray, m/z = 569.3 [M+H], RT 0.61 min;

tO Compound 198: MS, electrospray, m/z = 583.3 [M+H], RT 0.66 min (method B1 );

Resolution: LUX Amylose-2,21x250mm 35% (l:l:lMeOH:EtOH:iPA)+Et₂NH:CO₂, 80ml/min, llObar, 40°C

Compound 199: MS, electrospray, m/z = 583.3 [M+H], RT 0.66 min (method B1 ).

Resolution: LUX Amylose-2,21x250mm 35% (l:l:lMeOH:EtOH:iPA)+Et₂NH:C0₂, 80ml/min, 15 llObar, 40°C

The following compounds from Table 1 are prepared according to the procedure described in Example 7, usîng phénol, 2-8, bromîde, 6-39, and other appropriate starting materials and purification conditions:

Compound 17: MS, electrospray, m/z = 561.2 [M+H], RT 0.77 min;

Compound 18: MS, electrospray, m/z « 589.3 [M+H], RT 0.73 min;

Compound 19: MS, electrospray, m/z = 589.3 [M+H], RT 0.73 min;

Compound 20: MS, electrospray, m/z = 559.3 [M+H], RT 0.76 min;

Compound 21: MS, electrospray, m/z = 575.3 [M+H], RT 0.83 min;

Compound 22: MS, electrospray, m/z = 575.3 [M+H], RT 0.73 min.

The following compound from Table 1 is prepared according to the procedure described in

Example 7, using phénol, 2-9, bromide, 4-19, and olher appropriate starting matériels and purification conditions:

Compound 7: MS, electrospray, m/z = 547.2 [M+H], RT 0.71 min.

The following compounds from Table 1 are prepared according to the procedure described in Example 7, using phénol, 2-10, bromide, 4-19, and other appropriate starting matériels and purification conditions:

Compound 9: MS, electrospray, m/z = 581.2 [M+H], RT 0.73 min;

Compound 83: MS, electrospray, m/z = 609.4 [M+H], RT 0.79 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7, using phénol, 2-10, bromide, 4-21, and other appropriate starting materials and purification conditions:

Compound 93: MS, electrospray, m/z = 595.3 [M+H], RT 0.80 min.

The following compounds from Table 1 are prepared according to the procedure described in Example 7, using phénol, 2-10, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 84: MS, electrospray, m/z = 623.4 [M+H], RT 0.83 min;

Compound 88: MS, electrospray, m/z = 595.3 [M+H], RT 0.80 min;

Compound 107: MS, electrospray, m/z = 607.4 [M+H], RT 0.77 min;

Resolution: Chirapak AD-H, 30x250mm; 50%Isopropanol:Hexane with 1% lsopropylamine @ 88 mL/min, 100 bar CO₂, ambîent temp.

Compound 108: MS, electrospray, m/z = 607.4 [M+H], RT 0.77 min.

Resolution: Chirapak AD-H, 30x250mm; 50%lsopropanol:Hexane with 1% lsopropylamine @ 88 mL/min, 100 bar CO₂, ambient temp.

The following compounds from Table I are prepared according to the procedure described in

Example 7, using phénol, 2-11, bromide, 4-19, and other appropriate starting materials and purification conditions:

Compound 52: MS, electrospray, m/z = 547.3 [M-H], RT 0.70 min;

Compound 53: MS, electrospray, m/z = 575.3 [M-H], RT 0.71 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7, using phénol, 2-12, bromide, 4-19, and other appropriate starting materials and purification conditions:

Compound 63: MS, electrospray, m/z = 559.3 [M+H], RT 0.65 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7, using phénol, 2-13, bromide, 4-19, and other appropriate starting materials and purification conditions:

Compound 98: MS, electrospray, m/z = 555.4 [M+H], RT 0.76 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7, using phénol, 2-13, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 99: MS, electrospray, m/z = 569.4 [M+H], RT 0.79 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-14, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 124: MS, electrospray, m/z = 569.4 [M+H], RT 0.71 min

Example 7, using phénol, 3-15, bromide, 4-19, and other appropriate starting materials and purification conditions:

Compound 6: MS, electrospray, m/z = 541.2 [M+H], RT 0.73 min;

Compound 32: MS, electrospray, m/z = 527.3 [M+H], RT 0.73 min;

Compound 34: MS, electrospray, m/z = 569.3 [M+H], RT 0.71 min;

Compound 35: MS, electrospray, m/z = 555.3 [M+H], RT 0.71 min;

Compound 36: MS, electrospray, m/z = 569.3 [M+H], RT 0.73 min;

Compound 110: MS, electrospray, m/z = 555.4 [M+H], RT 0.75 min;

Resolution: ChiralPak AD-H Prep 30% EtOH:COj @ 80 ml/min., 100 bar, 25°C Compound 112: MS, electrospray, m/z = 555.4 [M+H], RT 0.75 min.

Resolution: ChiralPak AD-H Prep 30% EtOH:CO2 @ 80 ml/min., 100 bar, 25°C

The following compound from Table 1 is prepared according to lhe procedure described in Example 7, using phénol, 3-15, bromide, 4-22, and other appropriate starting materials and purification conditions:

Compound 245: MS, electrospray, m/z = 583.1 [M+H], RT 0.62 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7, using phénol, 3-15, bromide, 4-23, and other appropriate starting materials and 20 purification conditions:

Compound 131: MS, electrospray, m/z = 585.4 [M+H], RT 1.21 min (Method B1);

The following compound from Table 1 is prepared according lo the procedure described in 25 Example 7, using phénol, 3-15, bromide, 4-24, and other appropriate starting materials and purification conditions:

Compound 205: MS, electrospray, m/z = 583.3 [M+H], RT 0.67 min (Method Bl);

Compound 213: MS, electrospray, m/z = 555.3 [M+H], RT 0.67 min (Method Bl);

The following compounds from Table 1 are prepared according to the procedure described in Example 7, using phénol, 3-15, bromide, 5-34, and other appropriate starting matériels and purification conditions:

Compound 114: MS, electrospray, m/z = 583.5 [M+H], RT 0.62 min;

Compound 125: MS, electrospray, m/z = 569.4 [M+HJ, RT 1.25 min (Method B2);

Resolution: LUX 5u Cellulose 2 Prep, 23% MeOH (1% Et2NH) in CO2 at 78ml/min over 21 minutes, 160 Bar, 40°C.

Compound 126: MS, electrospray, m/z = 569.4 [M+H], RT 1.25 min (Method B2); Resolution: LUX 5u Cellulose 2 Prep, 23% MeOH (1% Et2NH) in CO2 at 78ml/min over 21 minutes, 160Bar,40°C.

Compound 128: MS, electrospray, m/z = 583.5 [M+H], RT 1.31 min (Method B2);

Résolution: Chiralcel OD-H, 20x250mm 5.8% MeOH (~1% Et2NH) in CO2 at 85g/min, 160 Bar, 40C.

Compound 129; MS, electrospray, m/z = 583.5 [M+H], RT 1.31 min (Method B2);

The following compound from Table I is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 4-23, and olher appropriate starting materials and purification conditions:

Compound 216: MS, elecirospray, m/z = 555.3 [M+H], RT 0.64 min (Method Bl); Compound 247: MS, electrospray, m/z « 557.1 [M+H], RT 1.21 min (Method B2);

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 5-34, and olher appropriate siartîng materials and purification conditions:

Compound 146: MS, electrospray,m/z = 597.4[M+H], RT0.65 min(Melhod Bl);

Compound 152: MS, electrospray,m/z = 597.4 [M+H], RT0.65 min (Method Bl);

Résolution: Chiralcel OD-H, 20x250mm 5.8% MeOH (~l% Et₂NH) in CO₂ at 85g/min, 160 Bar, 40°C;

Compound 153: MS, electrospray, m/z = 597.4 [M+H], RT 0.65 min (Method Bl);

Resolution: Chiralcel OD-H, 20x250mm 5.8% MeOH (~l% Et₂NH) in CO₂ at 85g/min, 160 Bar, 40°C;

Compound 155: MS, electrospray, m/z = 613.4 [M+H], RT 0.55 min (Method Bl);

Compound 156: MS, electrospray, m/z = 573.4 [M+H], RT 0.43 min (Method B1);

Compound 163: MS, electrospray, m/z - 625.3 [M+H], RT 0.77 min;

Compound 164: MS, electrospray, m/z - 555.3 [M+H], RT 0.71 min;

Compound 172: MS, electrospray, m/z = 597.3 [M+H], RT 1.31 min (Method B2);

Compound 179: MS, electrospray, m/z = 613.1 [M+H], RT 0.67 min (Method Bl);

Compound 189: MS, electrospray, m/z = 583.5 [M+H], RT 0.63 min

Compound 193: MS, electrospray, m/z = 583.51 [M+H], RT 0.63 min

Compound 208: MS, electrospray, m/z = 587.3 [M+H], RT 1.48 min (Method B2);

Compound 236: MS, electrospray, m/z - 597.3 [M+H], RT 1.54 min (Method A2); Résolution: LUX 5u Cellulose I Prep 7% EtOH:Heptane @ lOml/min

Compound 238: MS, electrospray, m/z = 569.2 [M+H], RT 0.60 min;

The following compound from Table I is prepared according to the procedure described in Example 7a, using phénol, 3-17, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 135: MS, electrospray, m/z = 611.5 [M+H], RT 0.86 min;

Compound 136: MS, electrospray, m/z = 611.5 [M+H], RT 0.83 min;

Compound 137: MS, electrospray, m/z = 597.5 [M+H], RT 0.84 min;

The following compound from Table I is prepared according lo the procedure described in Example 7a, using phénol, 3-18, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 148: MS, electrospray, m/z = 609.4 [M+H], RT 0.81 min;

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-19, bromide, 5-34, and other appropriate starting matériels and 5 purification conditions:

Compound 133: MS, electrospray, m/z = 597.5 [M+H], RT 0.81 min.

The following compound from Table I is prepared according to the procedure described in to Example 7a, using phénol, 3-20, bromide, 5-34, and other appropriate starting matériels and purification conditions:

Compound 134: MS, electrospray, m/z = 611.5 [M+H], RT 0.85 min;

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-21, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 149: MS, electrospray, m/z = 613.3 [M+H], RT 0.74 min;

Compound 150: MS, electrospray, m/z = 599.5 [M+H], RT 0.72 min;

Compound 151: MS, electrospray, m/z = 613.3 [M+H], RT 0.74 min;

Example 7a, using phénol, 3-22, bromide, 4-19, and other appropriate starting materials and 25 purification conditions:

Compound 183: MS, electrospray, m/z = 573.1 [M+H], RT 0.53 min.

Example 7a, using phénol, 3-22, bromide, 5-34, and other appropriate starting materials and 30 purification conditions:

Compound 182: MS, electrospray, m/z = 585.9 [M+H], RT 0.55 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-22, bromide, 4-19, and other appropriate starting materials and 5 purification conditions:

Compound 181: MS, electrospray, m/z = 570.7 [M+H], RT 0.61 min.

The following compound from Table 1 is prepared according to the procedure described in to Example 7a, using phénol, 3-22, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 180: MS, electrospray, m/z = 583.7 [M+H], RT 0.64 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-22, bromide, 4-19, and other appropriate starting materials and purification conditions:

Compound 209; MS, electrospray, m/z = 541.4 [M+H], RT 0.52 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-22, bromide, 5-34, and other appropriate starting materials and purification conditions:

Compound 224: MS, electrospray, m/z = 556.7 [M+H], RT 0.52 min.

Example 8: Préparation of 5-ethoxy-l-(6-|2-|2-(2-fluoro-l-methyl-ethyl)-l,2,3«4tetrahydro-lsoquinolin-6-ylmethoxy]-3-methyl-phenyl}-pyridln-2-yl)-llI-pyrazole-4carboxyllc acid (49)

Amine, 8-42 (2.94 g, 5.74 mmol) is dissolved in méthanol (20 mL), THF (20 mL) and water (10 mL). To this solution is added LiOH (0.97! g, 40.60 mmol) and the mixture is heated at 50 °C for 2 h. The reaction is cooled to room température and concentrated in vacuo. The crude product is purified by reverse phase column chromatography on C18 (using a solvent gradient of

5- 95% MeCN/H₂O + 0.1% TFA) to provide 60 (2.94 g). MS, electrospray, m/z = 485.! [M+H], RT 0.68 min).

Amino acid 60 (78.0 mg, 0.15 mmol) is combined with 4A molecular sieves (20 mg), l-fluoropropan-2-one (100 pL), AcOH (25.0 pL), and Na(CN)BHj (29.2 mg, 0.44 mmol) in MeOH (4 mL). The mixture is stirred at room température for 30 min and then heated to 50 °C for 12 h. lt is then concentrated under N₂, triturated with !:l MeOH/DMSO, fîltered through a 0.45 micron syringe filter, and the filtrate is purified by gradient elution (! 0-100% MeCN/water + 0.1%

HCO2H) on a Gilson RP-HPLC. Concentrated in vacuo to afford title compound 49 (70.0 mg). MS, electrospray, m/z » 545.3 [M+H], RT 0.72 min.

The following compounds from Table 1 are prepared according to the procedure described in Example 8, using appropriate starting materials and purification conditions:

Compound 64: MS, electrospray, m/z = 583.4 [M+H], RT 0.70 min;

Compound 65: MS, electrospray. m/z = 597.4 [M+H]. RT 0.75 min;

Compound 66: MS, electrospray, m/z » 597.4 [M+H], RT 0.72 min;

Compound 67: MS, electrospray, m/z = 625.5 [M+H], RT 0.78 min;

Compound 68: MS, electrospray, m/z = 569.4 [M+H], RT 0.68 min;

Compound 69: MS, electrospray, m/z = 583.4 [M+H], RT 0.70 min;

Compound 70: MS, electrospray, m/z = 605.4 [M+H], RT 0.71 min;

Compound 71: MS, electrospray, m/z = 569.4 [M+H], RT 0.71 min;

Compound 76: MS, electrospray, m/z = 597.4 [M+H], RT 0.79 min;

Compound 77: MS, electrospray, m/z = 569.4 [M+H], RT 0.69 min;

Compound 78: MS, electrospray, m/z = 583.4 [M+H], RT 0.71 min;

Compound 79: MS, electrospray, m/z = 597.4 [M+H], RT 0.75 min;

Compound 80: MS, electrospray, m/z = 611.4 [M+H], RT 0.74 min;

Compound 94: MS, electrospray, m/z = 587.4 [M+H], RT 0.80 min;

Compound 95: MS, electrospray, m/z = 597.4 [M+H], RT 0.82 min.

The following compounds from Table 1 are prepared according to the procedure described in Example 8, using phénol, 3-16, bromide, 4-19, and other appropriate starting materials and purification conditions:

Compound 50: MS, electrospray, m/z = 505.2 [M+H], RT 0.66 min;

Compound 51 : MS, electrospray, m/z = 561.3 [M+H], RT 0.70min;

Compound 54: MS, electrospray, m/z = 589.3 [M+H], RT 0.72 min;

Compound 55: MS, electrospray, m/z = 575.2 [M+H], RT 0.71 min;

Compound 56: MS, electrospray, m/z = 563.3 [M+H], RT 0.74 min;

Compound 57: MS, electrospray, m/z = 623.3 [M+H], RT 0.80 min;

Compound 58: MS, electrospray, m/z = 563.2 [M+H], RT 0.76 min.

Example 9: Préparation of Intermediate 3,3-dinuoro-cydobutanecarbaldehyde (9-44)

Dess-Martln

DCM

9-43

9,44

Dess-Martin periodinane (2.6 g, 6.1 mmol) is added to a mixture of 3,3difluorocyclobutylmelhanol, 9-43, (0.5 g, 4.0 mmol) and NaHCOj (1.4 g, 16.0 mmol) in dichloromethane (10 mL) at room température. The resulting slurry is stirred in the dark for 15 h and then poured into a solution of saturated aqueous NaHCOj. The resulting mixture is filtered through a hydrophobie frit with excess dichloromethane. The organic filtrate is washed with saturated aqueous Na2S₂O5, and then separated with another hydrophobie frit. The filtrate is dried over MgSOi, and then filtered through a pad of diatomaceous earth using dichloromethane. Ali but about 5 mL of dichloromethane is removed by short path distillation at atmospheric pressure (50 °C bath température). The remaining solution is cooled to -78 °C for 15 min to precipitate residual periodinane solids. The solvent is removed by syringe and passed through a 0.45 micron Millipore fiiter. The filtrate containing the crude aldéhyde 9-44 (Ό.IM in dichloromethane) is used as is without further purification or concentration.

Example 10: Préparation of l-(6-{2-|2-(33-dlfluoro-cyclobutylmethyi)-1^3,4-tetrahydroisoquinolîn-6-yimethoxy|-3-methyl-phenyi}-pyridin-2-yl)-5-isopropoxy-lII-pyrazoie-4carboxylic acid (4)

Amine 7-41 (56.0 mg, 0.1 i mmol) is combined with4A molecular sieves (20 mg), 3,3-difluorocyclobutanecarboxaidehyde, 9-44, (100 pL, 0.2 i mmol), AcOH (20 pL), and Na(CN)BHj (20.01 mg, 0.32 mmol) in MeOH (2.0 mL). The mixture is stirred at room température for 30 min, and then healed to 50 °C for i 2 h. The mixture is diluted with THF ( i .0 mL) and water ( 1.0 mL). To this is added LiOH (14.68 mg, 0.64 mmol) and the réaction is heated to 50 °C for 2 h. it is then concentrated under Ni, triturated with i:i MeOH/DMSO, filtered through a 0.45 micron syringe fiiter, and the filtrate is purified by gradient elution (10-100% MeCN/water + 0.1% HCO2H) on a Gilson RP-HPLC. Concentrated in vacuo to afford title compound 4 (40.0 mg). MS, electrospray, m/z = 603.4 [M+H], RT 0.78 min.

The following compounds from Table 1 are prepared according to the procedure described in Example 10, using the appropriate amine, other appropriate starting materials and purification conditions:

Compound 26: MS, electrospray, m/z - 575.3 [M+H], RT 0.73 min; Compound 29: MS, electrospray, m/z = 589.3 [M+H], RT 0.77 min;

Compound 82: MS, electrospray, m/z = 561.3 [M+H], RT 0.82 min;

Compound 96: MS, electrospray, m/z = 589.4 [M+H], RT 0.96 min.

Example 11; Préparation of intermediate 2,2-difluoro-cyclopropanecarbaldehyde (10-46)

O

11-45

EDCI

DIPEA, DCM

F F A O	DIBAL-H ^FV^F DCM
11-46	11-47

EDCI (1.4g, 7.1 mmol) is added to a mixture of Ν,Ο-dimethylamine hydrochloride (600 mg, 6.2 mmol) and 2,2-difluorocyclopropane carboxylic acid, 11-45, (580 mg, 4.8 mmol) in dichloromethane (15 mL) at room température. Ν,Ν-Diisopropylethylamine (3.3 mL, 19.0 mmol) is added and the mixture is stirred for 3 h. A solution of IN HCl is added, followed by vigorous stirring for 10 min. The organic phase is separated using a hydrophobie frit and applied directly to a 10 g SiO₂ samplet. The crude matériel is purified on a 50 g HP-Sil SNAP cartridge (Biotage) eluting with 9:1 dichloromethane/MeOH. The solvent is removed from product containing fractions via short-path distillation at atmospheric pressure (bath temp of 70 °C) to afford 11-46 (605 mg).

A solution of 11-46, (605 mg, 3.66 mmol) in dichloromethane at -78 °C is lreated dropwîse with D1BAL-H (4.2 mL, 1.0 M in dichloromethane) and then is stirred 2.5 h at -78 °C. The reaction is quenched by addition of saturated aqueous Rochelle sait solution. An equai volume of water is added and the mixture is warmed to room température. The mixture is vigourously stirred for 3 h, followed by séparation of the organic phase with a hydrophobie frit. The dichloromethane is removed by short path distillation at atmospheric pressure (bath temp - 62 °C) to afford 11-47 (389 mg).

Example 12: Préparation of l-(6-(2-[2-(2^-difluoro-cyclopropylmethyl)-l,23»4-tetrahydrolsoquinolin-6-ylmethoxy]-3-methyI-phenyI]-pyridin-2-yl)-5-methoxy-lH-pyrazole-4carboxyllc acid (72)

THF, UOH MeOH, H,O

12-48

1. Na(CN)BH,

MeOH, AcOH

11-47

Amine 12-48 (90.0 mg, 0.18 mmol) is combined with 4Â molecular sieves (20 mg), 2,2-difluorocyclopropanecarboxaldehyde, 11-47, (60.0 mg, 0.54 mmol), AcOH (20 pL), and Na(CN)BHj (34.0 mg, 0.54 mmol) in MeOH (4.0 mL). The mixture is stirred at room température for 30 min, and then heated to 50 ^QC for 12 h. The mixture is diluted with THF (1.0 mL) and water (1.0 mL). To this is added LiOH (33.00 mg, 1.43 mmol) and the reaction is heated to 50 °C for 2 h. It is then concentrated under N₂, triturated with 1:1 MeOH/DMSO, filtered through a 0.45 micron syringe fîlter, and the filtrate is purified by gradient elution (10-100% MeOH/water + 0.1% HCO₂H) on a Gilson RP-HPLC. Concentrated in vacuo to afford title compound 72 (7.0 mg). MS, electrospray, m/z = 561.3 [M+H], Method A2, RT 1.59 min.

Example 13: Préparation of 5-methoxy-l-(6-(3-methyl-2-[2-(2,2,2-trinuoro-ethyl)-l,2,3,4tetrahydro-isoquinolin-6-ylmethoxy]-phenyl]-pyrldln-2-yl)-lH-pyrazoIe-4-carboxyIic acid (11)

13-49

1,01 PEA, MeCN

2, THF. UOH MeOH. HjO

2,2,2-Trifluoroethyl triflate, 13-49, (36.0 uL, 0.23 mmol) is added to a mixture of intermediate 12-48 (106.0 mg, 0.21 mmol) and N,N-diisopropylethylamine (190 pL, 1.10 mmol) in MeCN (5.0 mL). The mixture is heated to 45 °C for 4 h and then concentrated in vacuo. The remaining residue is redissolved in 5 mL ofTHF/MeOH/water (2:2:1) and treated with LiOH (25.0 mg, 1.10 mmol). The mixture is then heated to 50 °C for 2 h prior to removal of the solvents in vacuo. The remaining crude residue is purified by gradient elution on a 30 g KP-C18 SNAP cartridge (Biotage) using a gradient of 5-95% MeCN/water + 0.1% TFA to afford title compound 10 11 (103 mg). MS, electrospray, m/z = 553.2 [M+H], Method A2, RT 1.13 min.

Example 14: Préparation of Intermediate l-methyl-5-oxo-pyrrolldlne-3-carbaldehyde (1451)

1+50 1+51

Alcohol 14-50 (0.20 g, 1.55 mmol) is combined with polystyrene-bound 1BX resin (5.81 g) in dichlorométhane (20.0 mL) in a sealed 40 mL vial and is rotated end over end for 20 h. The reaction mixture is filtered away from the resin, and the resin is rinsed several times [first with dichlorométhane (10 mL), then with a 1:1 dichloromethane/MeOH (20 mL), again with 1:1 dichlorométhane /MeOH (20 mL), and finally with dichlorométhane (10 mL)]. The combined filtrâtes are concentrated under a stream of Nî to yield a mixture of 14-50 and desired product 14-51.

Example 15: Préparation of 5-ethoxy-l-(6-(3-methy!-2-[2-(l-methyl-5-oxo-pyrro!idin-3y!methy!)-l,23,4-tetrahydro-isoquino!in-6-ylmethoxy]-pheny!|-pyridin-2-yl)-lH-pyrazo!e

4-carboxylic acid (97)

HN.

Amino acid 60 (40.0 mg, 0.07 mmol) is combined with 4Â molecular sieves (20 mg), 14-51 (51.0 mg, 0.200 mmol), AcOH (15.0 pL), and Na(CN)BH₃ (13.2 mg, 0.20 mmol) in MeOH (2.0 mL). The mixture is stirred at room température for 30 min and then heated to 50 °C for 12 h. The crude is purified by reverse phase column chromatography on Ci8 (using a solvent gradient of5-95% MeCN/H₂O + 0.1% TFA) to afford title compound 97 (27.0 mg). MS, electrospray, m/z = 596.4 [M+HJ, RT 0.80 min.

Example 16: Préparation of 5-ethoxy-I-(6-{3-methyl-2-|2-(tetrahydro-furan-2-ylmethyl)- l,2,3,4-tetrahydro-isoquino!in-6-ylmethoxy]-phenyl)-pyridin-2-yl)-IH-pyrazo!e-4carboxylic acid (101)

To a mixture of amine 8-42 ( 100.0 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (1.00 mL) is added 2-bromomethyltetrahydrofuran (8.0 mg, 0.05 mmol) in DMF (0.06 mL). The mixture is irradiated at 100 °C for 10 min and cooled to room température. Excess bromide (76.0 mg) is added and the reaction is irradiated multiple times and then stirred at room température for 24 h. The réaction mixture is filtered and the filtrate is purified by HPLC (using a solvent gradient of 10-95% MeCN/H₂O + 0.1% Formic Acid) to provide 16-52 (6.0 mg).

16-52 (6.0mg) is dilutedwithTHF(l.OmL),water(l.OmL) and MeOH (1.0mL). Tothis is added LiOH (5.0 mg) and the reaction is heated to 50 °C for 2 h. The reaction mixture is cooled to room température, acidified with 4 N HCl in 1,4-dioxane, and filtered. The filtrate is purified by HPLC (using a solvent gradient of 10-95% MeCN/H₂O + 0.1% Formic Acid) to provide title compound 101 (1.0 mg). MS, electrospray, m/z « 569.4 [M+H], RT 0.88 min.

The following compound from Table 1 is prepared according to the procedure described in Example 16, using the appropriate starting materials and purification conditions:

Compound 138: MS, electrospray, m/z = 639.4 [M+H], RT 1.16 min; Compound 160: MS, electrospray, m/z = 563.3 [M+H], RT 0.96 min.

Example 17: Préparation of l-(6-[2-[2-(2-hydroxy-2-metliyl-propyl)-l,2,3»4-tetraliydroisoquinoiin-6-yImethoxy|-3-methyl-phenyl}-pyridin-2-yi)-5-methoxy-lII-pyrazoie-4carboxylic acid (33)

12-48

17-53

Intermediate 12-48 (90.0 mg, 0.i8 mmol) is dissolved in MeCN (5.0 mL) to which is added Cs₂COj (117.9 mg, 0.36 mmo) and chloride 17-53 (29,5 mg, 0.27 mmol). The mixture is heated to 50 °C for 10 h. The reaction was cooled, extracted with EtOAc, washed with brine, dried over MgSO«, and concentrated. The resulting matériel is purified by gradient elution on a 30 g KPC18 SNAP cartridge (Biotage) using a gradient of 15-65% MeCN/water + 0.1% TFA to afford the intermediate ester. Theesterisdissolved in 5 mLofTHF/MeOH/water(2:2:i) and treated wilh LiOH (25.0 mg, 1.10 mmol). The mixture is then heated to 50 °C for 2 h prior to removal of the solvents in vacuo. The remaining crude residue is purified by gradient elution on a 30 g KP-C18 SNAP cartridge (Biotage) using a gradient of 15-65% MeCN/water + 0.1% TFA to afford tille compound 33 (103.0 mg). MS, electrospray, m/z = 543.2 [M+H], RT 0.68 min.

The following compound from Table i is prepared according lo the procedure described in Example 17, using the appropriate starting matériels and purification conditions:

Compound 74; MS, electrospray, m/z = 577.3 [M+H], RT 0.67 min; Compound 168: MS, electrospray, m/z = 587.3 [M+H], RT 0.70 min.

Example 18: Préparation of 6-Bromomethyl-8-trifluoromethyl-3,4-dlhydro-lII i$oquinollne-2-carboxylic acid tert-butyl ester (18-10)

18-1

SOCI₂: then NaCN

18-2

1) CH₂O.HCO₂H

2) 48%aq HBr

3) BoCjO, 4-DMAP, ΕΙ,Ν

18-4

>I₂W Et₃N	ΥΥΊ

	F-T	'F
	F
		1841

vinylboronic acid-pyridlne complex Pd(PPh₃)„ aq. Na₂CO₃

18-9

Commercial acid 18.1 (5.0g, 22.7 mmol) is dissolved in THF (30 mL) at rt. A IM solution of borane in THF (34.0 mL, 34.0 mmol) is added dropwise via syringe. The mixture is then heated to 55 °C o/n before cooling to rt and quenching with water (5 mL). After stirring for 5 min, 12 mL of 2N HCl is added and the mixture is sttrred lh. dichloromethane (50 mL) and water (50 mL) are then added, and the resulttng phases are separated wtth a hydrophobie frit. The organic layer is further dried over NajSCh, then reftitered. Concentrated in vacuo to affords an oil that is purified by gradient elution (5-100% EtOAc/heptane) on a 100g KP-Sil SNAP cartridge (Biotage). Concentration of the product fractions delivers intermediate 18.2 (3.2 g)

Thionyl chloride (SOC1₂) (2.3 mL, 31.5 mmol) is added to a solution ofalcohol 18.2 (3.2 g, 15.5 mmol) in dichloromethane (20 mL) under N₂at-10 °C. Aller 5 min, the cooling bath isremoved and the mixture is heated to reflux for 6h. The resulting solution is cooled to rt and concentrated in vacuo. The remaining residue is then azeotroped with PhMe (2x10 mL) and then dissolved in DMF (20 mL). Solid NaCN (840 mg, 17.1 mmol) is added and the mixture is heated to 45 °C o/n. Upon cooling to rt, the mixture is diluted with water(25 mL), brine (25 mL), and EtOAc (50 mL). The layers are separated, and the organics are dried over Na₂SO4, fîltered, and concentrated in vacuo. Crude product is purified by gradient elution (5-100% EtOAc/heptane) on a 100g KP-Sil SNAP cartridge (Biotage). Product fractions concentrated in vacuo to afford 18-3 (3.0 g).

A IM solution of borane in THF (35 mL, 35 mmol) is added dropwise via syringe to a solution of 18-3 (3.0 g, 13.9 mmol) in THF (25 mL) at rt. The mixture is then heated to 55 °C o/n before cooling to rt, and quenching with water (5 mL). Aller 5 min of stirring, conc. HCl (8 mL) is added and stirring is continued for Ih. The mixture is then diluted with water (20 mL), and treated with solid NaOH until alkaline. dichloromethane (50 mL) and brine (25 mL) are added, then the layers are separated with a hydrophobie frit. The crude amine is purified by gradient elution (5-95% MeCN/water + 0.1% TFA) on a 120g KP-C18 SNAP cartridge (Biotage). Concentration of the fractions in in vacuo affords an intermediate TFA sait (2.93 g) that is dissolved in HCO₂H (30 mL) and treated with 37% aq. HCHO (0.66 mL, 8.8 mmol). The mixture is stirred at 50 °C o/n, then concentrated in vacuo to afford a crude solid that is immediately dissolved in 48% aq. HBr (25 mL). This solution is heated to 100 °C o/n, then concentrated in vacuo. The crude matériel is azeotroped with PhMe (3x15 mL), then slurried in dichloromethane (50 mL) and DMF (10 mL). EtjN (1.9 mL, 0.82 mmol) and a few crystals of4DMAP are added. Boc₂O (2.0 g, 9.1 mmol) is added in one portion, and the mixture is stirred at rt o/n. Saturated NH4C1 solution (50 mL) is added and the layers are separated with a hydrophobie frit. The organic is concentrated in vacuo to afford a crude residue that is purified by gradient elution (5-100% EtOAc/heptane) on a 100g KP-Sil SNAP cartridge (Biotage). Concentration of the product fractions afforded 18-5 (540 mg).

Tf₂O (0.27 mL, 1.6 mmol) is added via syringe to a mixture of 18-5 (540 mg, 1.46 mmol), EtjN (0.31 mL, 2.2 mmol) and 4-DMAP (18 mg, 0.15 mmol) in dichloromethane (25 ml) cooled to 0 °C. The mixture is stirred with warming to rt o/n, and then quenched with sat. NaHCOj (30 mL). The resulting layers are separated with a hydrophobie frit, and the organics are concentrated under N₂. The crude residue is purified by gradient elution (5-30% EtOAc/heptane) on a 50g HP-Sil SNAP cartridge (Biotage). Concentration of the product fractions in vacuo affords 18-6 (460 mg).

Triflate 18-6 (460 mg, 1.02 mmol) is combined with vinylboronic aeîd-pyridine complex (250 mg, 1.04 mmol) and Pd(PPh₃)4 (60 mg, 0.05 mmol) in a mixture of DME (9 mL) and 2M aq. Na₂CO₃ solution. The mixture is irradiated in Biotage microwave at 120 “C for 40 min. Upon cooling, then mixture is concentrated under N₂, and the crude solide and triturated with dichloromethane. The dichloromethane filtrate is then purified by gradient elution (5-80% EtOAc/heptane) using a 50g HP-Sil SNAP cartridge (Biotage). Product fractions concentrated in vacuo to afford 18-7 (275 mg).

Styrene 18-7 (275 mg, 0.84 mmol) and NaïOi (630 mg, 2.95 mmol) are combined in a mixture of THF (12 mL) and water (3 mL) at rt. OsO^ (0.13 mL, 0.017 mmol, 4 wt% in H₂O) is added via syringe and the resulting slurry is stirred vigorously o/n at rt. The slurry is then filtered through a frit, and concentrated in vacuo. The remaining residue is dissolved in dichloromethane (20 mL), and washed with saturate aq. thiosulfate solution (25 mL). The layers are then separated with a hydrophobie frit, and the organic concentrated in vacuo. Purification of the crude residue by gradient elution (5-60% EtOAc/heptane) on a 25g HP-Sil SNAP cartridge (Biotage) affords 18-8 (228 mg).

Aldéhyde 18-8 (225 mg, 0.683 mmol) îs dissolved in THF (5 mL) and then MeOH (5 mL). Solid NaBH< (40 mg, 1.1 mmol) is added, and the mixture is stirred at rt for 20 min. Aqeous sat. NH4CI (ca 50 mL) is added and the mixture is stirred for 15 min. EtOAc (100 ml) and brine (100 mL) are added, then the layers are separated. The organic is dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product is purified by gradient elution (5-100% EtOAc/heptane) on a 50g HP-Sil SNAP cartridge (Biotage). Concentration of the product fractions in vacuo affords 18-9 (225 mg).

Solid PhjPBr₂ (450 mg, 1.02 mmol) is added to a mixture of 18-9 (225 mg, 0.68 mmol) and DIPEA (0.21 mL, 1.2 mmol) in dichloromethane at 0 °C. The mixture is stirred for 1 hour, and then concentrated in vacuo. The crude bromide is purified by gradient elution (5-40% EtOAc/heptanes) on a 25g HP-S11 SNAP cartridge (Biotage) to afford 18-10 (248 mg).

Similarly, the following bromides were prepared from the appropriate starting materials as described in Example 18:

18-11	^F Ύ
18-12	''δΟγΟ
18-13	Ύ

Example 7a, using phénol, 2-8, bromide, 18-10, and other appropriate starting materials and purification conditions:

Compound 158: MS, electrospray, m/z » 623.3 [M+H], RT 1.34 min (Method B2).

The following compound from Table l is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 18-10, and other appropriate starting materials and purification conditions:

Compound 157: MS, electrospray, m/z = 637.3 [M+H], RT 0.67 min (Method B2).

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 18-11, and other appropriate starting materials and purification condilions:

Compound 201: MS, electrospray, m/z = 573.3 [M+H], RT 1.14 min (Method B2);

Compound 202: MS, electrospray, m/z - 589.3 [M+H], RT 1.14 min (Method B2); Compound 229: MS, electrospray, m/z = 587.3 [M+H], RT 1.46 min (Melhod B2);

Resolution: LUX 5u Cellulose 3 Prep 14% (1:1:1 MeOH:EtOH:iPA):CO₂,40°C, HObar, 80ml/min

Compound 230: MS, electrospray, m/z « 559.3 [M+H], RT 1.46 min (Method B2). Résolution: LUX 5u Cellulose 3 Prep 14% (1:1:1 MeOH:EtOH:iPA):CO₂,40°C, 110 bar, 80ml/min

Compound 253: MS, electrospray, m/z = 559.4 [M+H], RT 1.20 min (Method A2) (Med Polar Long).

Compound 254: MS, electrospray, m/z = 559.3 [M+H], RT 1.20 min (Method A2) (Med Polar Long).

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 18-12, and other appropriale starting materials and purification conditions:

Compound 177: MS, electrospray, m/z = 545.2 [M+H], RT 0.68 min (Method Bl);

Compound 187: MS, electrospray, m/z = 575.3 [M+H], RT 1.13 min (Method B2);

Compound 231: MS, electrospray, m/z = 589.3 [M+H], RT 1.26 min (Method B2);

Resolution: LUX 5u Cellulose 4 Prep 20% 1:1:1 MeOH:EtOH:iPA (0.1% Et₂NH):CO₂ @ 75 ml/min., 130 bar, 40°C

Compound 234: MS, electrospray, m/z = 589.3 [M+H], RT 1.26 min (Method B2);

Compound 251: MS, electrospray, m/z = 559.4 [M+H], RT 1.18 min (Method A2) (Med Polar Long).

Resolution: ChiralPak AD-H Prep 45% 3:1 hexane:EtOH (1% iPrNH₂):CO₂ @ 80 ml/min., 100 10 bar, 25°C

Compound 252: MS, electrospray, m/z = 559.3 [M+H], RT 1.18 min (Method A2) (Med Polar Long).

Resolution: ChiralPak AD-H Prep 45% 3:1 hexane:EtOH (1% iPrNH₂):CO₂ @ 80 ml/min., 100 bar, 25°C

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 18-13, and other appropriate starting materials and purification conditions:

Compound 166: MS, electrospray, m/z = 623.3 [M+H], RT 1.30 min (Method B2).

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 18-12, and other appropriate starting materials and purification conditions:

Compound 159: MS, electrospray, m/z = 587.3 [M+H], RT 0.61 min (Method Bl).

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 18-13, and other appropriate starting materials and purification conditions:

Compound 165: MS, electrospray, m/z = 637.3 [M+H], RT 1.42 min (Method B2).

Example 19: Préparation of intermediate 7-Hydroxymethyl-6-methyl-l,2,4,5tetrahydro-benzo|d|azepine-3-carboxylic acid tert-butyl ester (19-14)

NaCN, DMF

LAH, THF

r.l. 5 h

19-2

SOC12, DCM rt,4h

1. (CDCI)2. DMF

DCM.rt.2h

KOH, EtOH reflux. 5 h ri, 12 h

19-5

2. E13N. DCM, r.t,4h h₂n^Y^OW9OMb

BMS, Toluene reflux, 3 h

Tf,O. Py.. DCM

-50 °C - fl. 2 h

19-11

LAH,THF

-40C,2h

A solution of compound 19-1 (100g, 0.465 mol) in THF (800.000 ml) is added to a mixture of LAH (166g, 1.395 mol) in anhydrous THF (200 ml) at 0 °C. The mixture is stirred at room température for 0.5 h, then is refluxed for 1 h. TLC showed the reaction is completed. A saturated aqueous NH4CI (200 ml) is slowly added to the mixture. Then EtOAc and Na₂SO4 are added. The mixture is stirred for 1 h, and then is filtered and washed by PE to afford compound 19-2.

To a solution of compound 19-2J360.000 g, 2.365 mol) in dichloromethane (3000.000 ml) is added SOC1₂ (562.980 g, 4.731 mol) at -10 °C. Then the reaction mixture is refluxed for 4 h. The mixture is concentrated to a fiord crude compound 19-3 which is used directly in the next step.

A mixture of compound 19-3 (334.000 g, 1.957 mol) and NaCNJ 168.096 g, 2.290 mol) in DMF (1000.000 ml) is stirred at room température ovemight. The mixture is extracted with EtOAc and H₂O. The organic layer is dried and concentrated, and purified by chromatography on silica gel (PE: EA = 50:1) to give compound 19-4 as a yellow oil.

A mixture of compound 19-4 (1608.000 g, 9.975 mol), KOH (1117.221 g, 19.950 mol) in E1OH (15000.000 ml) is heated to reflux for 5 h. TLC showed the reaction is completed. The solvent is removed under reduced pressure. The residue is adjusted to pH = 1. The mixture is filtered and the filter cake is dried to yield compound 19-5.

Compound 19-5 (737.000 g, 4.090 mol) is added to a stirred solution of (COCI)₂ (8.180 mol) and DMF (70.000 ml) in dichloromethane (7370.000 ml) under N₂ atmosphère, followed by stirring for 2 h. TLC showed the reaction is completed. Then the mixture is evaporated. The residue was added to a stirred solution of 2,2-dimethoxyethyl-l-amine (429.996 g, 4.090 mol) and EtjN (454.388 g, 4.499 mol) in dichloromethane (1000 ml) at room température for 2 h. TLC showed the reaction is completed. The mixture is evaporated and the residue is purified by column to give compound 19-6.

A solution of compound 19-6 (1053 g, 3.939 mol) in AcOH (2 L) and HCl (2 L) is stirred at room température for 16 h. TLC showed the reaction is completed. The mixture is evaporated. The residue is crystallized, washed with H₂O and EtOH, and then the solid is filtered and dried to give compound 19-7.

A mixture of Pd/C (4 g) and compound 19-7 (40.000 g, 0.197 mol) in AcOH (2 L) is stirred at room température under H₂ for 16 h. LCMS showed the reaction is completed. The mixture is fïltered, evaporated, and the residue is crystallized with EtOH. The solid is fïltered and dried to give compound 19-8.

To a stirred solution of compound 19-8 (130.000 g, 0.633 mol) in THF (1300.000 ml) is added

BMS,( 127.000 ml, 1.267 mol) slowly under N₂ atmosphère, meanwhile the température is maintained below -5 °C, followed by stirring for 16 h. LCMS showed the reaction is completed. The reaction is quenched with conc. HCl and then the mixture is refluxed for 2 h. The solvent is evaporated and the residue is separated with dichloromethane and H₂O. The aqueous phase is adjusted to pH = 9 and the solid is fïltered and dried to give compound 19-9.

A solution of compound 19-9 (220.000 g, 1.150 mol) in 48% HBr aqueous (1800.000 ml) is stirred at 110 °C for 4 h under N₂ atmosphère. LCMS showed the reaclion is completed. The mixture is evaporated to give crude compound 19-10.

A mixture of compound 19-10 (267.000 g, 1.506 mol), Boc₂O (492.595 g, 2.260 mol) and TEA (380.368 g, 3.766 mol) in dichloromethane (2670.000 ml) is stirred at room température for 2 h. The reaction is monitored by TLC. When compound 19-10 is consumed, the reaction mixture is concentraled under reduce pressure and the residue was purified by column chromatography to give compound 19-11.

A mixture of compound 19-11 (267.000 g, 0.963 mol)andTf₂O (271.468 g, 0.963 mol) in (2670.000 ml) is stirred at room température for 2 h under N₂ atmosphère. TLC showed the reaclion is completed. The reaction mixture is concentrated under reduce pressure and the residue is purified by column to give compound 19-12.

A mixture of compound 19-12 (20.000 g, 0.049 mol), dppp (2.000 g), Pd(OAc)₂ (2.000 g) and TEA (9.868 g, 0.098 mol) in EtOH (400.000 ml) is stirred at 80 °C for 12 h under CO atmosphère. The reaction is monitored by TLC. When the reaction is completed, the reaction mixture is concentrated under reduce pressure and the residue is purified by column chromatography to give compound 19-13.

To a stirred solution of compound 19-13 (22.000 g, 0.066 mol) in THF (300.000 ml) is slowly added LAH (2.507 g, 0.066 mol), meanwhile the température is maintained below -40 °C. After addition is completed, the mixture is stirred at room température for 2 h. TLC showed the reaction is completed and the reaction is quenched with H₂O. The solvent is removed under reduced pressure and the residue is separated with dichloromethane and H₂O, the organic phase îs dried over anhydrous Na₂SO₄, and evaporated. The residue was purified by column to give compound 19-14.

Bromination of the alcohol is performed similarly to that of Example 4 to yield intermediate 710 Bromomethyl-6-methyl-l,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester 1915.

19-15

The following compound from Table I is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 19-15, and other appropriate starting matériels and 15 purification conditions:

Compound 176: MS, electrospray, m/z = 555.3 [M+H], RT 1.19 min (MethodB2);

Compound 184: MS, electrospray, m/z = 583.3 [M+H], RT 1.24 min (MethodB2);

Compound 206: MS, electrospray, m/z = 569.3 [M+H], RT 1.26 min (MethodB2);

Resolution: LUX 5u Cellulose 4 Prep, 20% MeOH:EtOH:IPA (1:1:1) (0.1% Et₂NH) in CO₂ at 7O5ml/min, 130 Bar, 40°C.

Compound 207: MS, electrospray, m/z - 569.3 [M+H], RT 1.26 min (Method B2);

Resolution: LUX 5u Cellulose 4 Prep, 20% MeOH:EtOH:lPA (1:1:1) (0.1% Et₂NH) in CO₂ at 705ml/min, 130 Bar, 40°C.

Compound 222: MS, electrospray, m/z = 583.3 [M+H], RT 1.40 min (Method B2);

Resolution: LUX 5u Cellulose I Prep, 12% MeOHJPA (1% Et₂NH) in CO₂ at 70ml/min, 105 Bar, 40°C.

Compound 223: MS, electrospray, m/z = 583.4 [M+H], RT 1.42 min (Method B2); Resolution: LUX 5u Cellulose I Prep, 12% MeOHJPA (l% EtîNH) inCO2 at 70ml/min, 105 Bar, 40°C.

The following compound from Table I is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 19-15, and other appropriate starting materials and purification conditions:

Compound 162; MS, electrospray, m/z = 597.3 [M+H], RT 1.34 min (Method B2);

Compound 175: MS, electrospray, m/z « 569.3 [M+H], RT 1.31 min (Method B2); Compound 190: MS, electrospray, m/z = 597.2 [M+H], RT 0.63 min (Method Bl); Compound 196: MS, electrospray, m/z = 585.3 [M+H], RT 0.67 min (Method BI); Compound 203: MS, electrospray, m/z = 599.3 [M+H], RT 0.67 min(Method BI) Resolution: Chirapak AD-H, 20x250mm; 20%EtOH:Heptane@ 8 mL/min,, ambient temp.

Compound 204: MS, electrospray, m/z = 599.3 [M+H], RT 0.67 min (Method B1 ) Resolution: Chirapak AD-H, 20x250mm; 20%EtOH:Heptane@ 8 mL/min„ ambient temp. Compound 211: MS, electrospray, m/z = 613.3 [M+H], RT 1.43 min (Method B2); Resolution : LUX 5u Cellulose 1 Prep 20% iPA+EtjNHiHeptane @ 9ml/min Compound 212: MS, electrospray, m/z = 613.3 [M+H], RT 1.43 min (Method B2);

Resolution : LUX 5u Cellulose 1 Prep 20% iPA+Et2NH:Heptane @ 9ml/min Compound 214: MS, electrospray, m/z = 611.3 [M+H], RT 1.61 min (Method B2); Resolution: LUX 5u Cellulose I Prep 30% ÎPA:CO2,1 IObar, 75ml/min, 40°C Compound 215: MS, electrospray, m/z = 611.3 [M+H], RT 1.61 min (Method B2); Resolution: LUX 5u Cellulose I Prep 30% iPAîCCh, I IObar, 75ml/min, 40°C

Compound 225: MS, electrospray, m/z = 583.3 [M+H], RT 1.41 min (Method B2); Resolution: LUX 5u Cellulose 4 Prep 20% 1:1:1 MeOH:EtOH:iPA (0.1% Et₂NH) : CO₂ @ 75 g/min., 110 bar, 40°C

Compound 226: MS, electrospray, m/z = 583.3 [M+H], RT 1.44 min (Method B2);

Resolution: ESI Industries CC4 Prep 55% 1:1 hexane:MeOH (3% ÎPrOH, 0.1% ÎPrNH2):CO2 @ 30 80 ml/min., 100 bar, 25°C

Compound 227: MS, electrospray, m/z = 583.3 [M+H], RT 1.41 min (Method B2);

100

Resolution: LUX 5u Cellulose 4 Prep

20% 1:1:1 MeOH:EtOH:iPA (0.1% Et₂NH) : CO₂ @ 75 g/min., 110 bar, 40°C

Compound 235: MS, electrospray, m/z = 583.3 [M+H], RT 1.41 min (Method B2); Resolution: LUX 5u Cellulose 4 Prep

20% 1:1:1 MeOH:EtOH:iPA (0.1% Et₂NH) : CO₂ @ 75 g/min., 110 bar, 40°C

Compound 228: MS, electrospray, m/z = 583.3 [M+H], RT 1.44 min (Method B2);

Résolution: ESI Industries CC4 Prep 55% 1:1 hexane:MeOH (3% iPrOH, 0.1% iPrNH₂):CO₂ @ 80 ml/min., 100bar,25°C

Compound 232: MS, electrospray, m/z = 597.3 [M+H], RT 1.54 min (Method A2); Resolution: LUX 5u Cellulose 1 Prep 7% EtOH:Heptane @ lOml/min

Compound 233; MS, electrospray, m/z = 597.3 [M+H], RT 1.50 min (Method A2); Resolution: LUX 5u Cellulose 4 Prep 20% EtOH:CO₂,80ml/min, 1 lObar, 40°C

Compound 235: MS, electrospray, m/z = 597.3 [M+H], RT 1.50 min (Method A2); Resolution: LUX 5u Cellulose 4 Prep 20% EtOH:CO₂, 80ml/min, 1 lObar, 40°C

Example 20. Préparation of Intermediate 5-Bromomethyl-4,7-dimethyl-l,3-diliydrolsolndole-2-carboxylic acid tert-butyl ester (20-4).

Wilkinson'». EtOH

PPhj&'p DIPEA

20*3

20-4

To a 100 mL round bottom flask is added amine 20-1 (0.500 g, 4.13 mmol) which is dissolved in dichloromethane (15.0 mL). The reaction mixture is cooled to 0 °C and triethylamine (1.15 mL, 8.25 mmol) and BOC₂O (1.35 g, 6.19 mmol) arc added. The reaction is warmed to room température and stirred ovemight. The reaction is extracted with dichloromethane, washed with water and brine, dried over MgSO« and concentrated. The resulting residue is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptanes. The desired fractions are collected and concentrated yielding an oil (0.556 g).

101

Propargyl alcoho! (0.579 mL, 9.94 mmol) is added dropwise at 0 °C to a solution of diacetylene 20-2 (0.550 g, 2.49 mmol) in anhydrous ethano! (15.0 mL). Wilkinson's catalyst (0.229 g, 0.249 mmol) is added and the mixture is stirred for 16 h at room température. The crude reaction is concentrated and subjected to silica gel chromatography using a gradient of 10-80% EtOAc in heptanes. The desired fractions are collected and concentrated yielding an off-white solid (0.125

g)·

To a solution of alcohol 20-3 (125 mg, 0.451 mmol) and N,N-diisopropy!ethylamine (0. ! 18 mL, 0.676 mmol) in dichloromethane (5.0 mL) is added triphenylphosphine dibromide (297 mg, 0.676 mmol) at 0 °C. The reaction is stirred for 2 h and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using a gradient of 7-60% EtOAc in heptanes to yield the desired product 20-4 (35.0 mg) as a white solid.

The foüowing compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 20-4, and other appropriate starting materials and purification conditions:

Compound 145: MS, electrospray, m/z = 569,3 [M+H], RT 0.75 min;

Compound 246: MS, electrospray, m/z = 585.0 [M+H], RT 1.40 min (Method B2);

Example 21. Préparation of Intermediate 6-Bromomethyl-5,8-dlmethyI-3,4-dihydro-lIIisoquinoline-2-carboxylic acid tert-butyl ester (21-8).

102

21-7 21-S

Ketone 21-1 (14.00 g, 70.27 mmol) and pyrrolidine (8.71 mL, 106.0 mmol) are dissolved in toluene (60 mL) and the mixture is refluxed under Dean Stark. conditions for 24 h. The reaction is then concentrated in vacuo. The resulting residue is dissolved in toluene (60 mL) and treated with 4-hexen-3-one (8.32 mL, 70.27 mmol) and hydroquinone (0.080 g, 0.727 mmol). The solution is heated to reflux for 24 h and then diluted with EtOAc and washed with IN HCl. The combined organics are dried and concentrated in vacuo to afford a viscous oil. The material is purified by silica gel chromatography using a gradient of20-100% EtOAc in heptanes to afford a yellow solid (11.74 g).

A 1.0 M LiHMDS solution (42.95 mL) is added dropwîse to a solution of intermediate 21-2 (10.00 g, 35.79 mmol) in THF (50.0 mL) at -78 °C. This mixture is stirred at -78 °C for an additional 30 min. TMS-C1 (5.45 mL, 42.95 mmol) is added dropwîse and stirred at -78 °C for 2 h. The réaction is warmed to room température and diluted with diethyl ether (200 mL). This mixture is added to a saturated Na₂COj solution and the phases are separated. The combined organics are dried and concentrated in vacuo. The residue is dissolved in ACN (50.0 mL) and Pd(OAc)₂ (8.04 g, 35.79 mmol) is added. The resulting mixture is cooled in a water bath to maintain reaction temp below 35 °C and stirred ovemight. The reaction is flltered through celite and the filtrate is concentrated in vacuo. The residue is taken up in 200 mL EtOAc then treated

103 with 1.0 M TBAF solution (50.0 mL). This mixture is stirred for 30 min and then washed with IN HCl and 10% sodium thiosulfate solution. The organics are dried and concentrated. The material is purified by silica gel chromatography using a gradient of 20-80% EtOAc in heptanes to afford an off-white solid (6.11 g).

To a solution of starting material 21-3 (1.50 g, 5.4! mmol) in dichlorométhane (25.0 mL) at room température is added pyridine (0.871 mL, 10.82 mmol). The solution is cooled to -30 °C and TfjO (1.00 mL, 5.95 mmmol) is added dropwise. The reaction is stirred at -30 °C for ! h and then is warmed to room température. It is concentrated in vacuo and the residue is diluted 10 with EtOAc, wahsed with 1 N HCl, saturated NaHCOj, brine, dried over MgSO<, and concentrated. The resultîng material is purified by silica gel chromatography using a gradient of ! 2-100% EtOAc in heptanes to yield a white solid ( 1.61 g).

Triflate 21-4 (1.00 g, 2.44 mmol) is combined with the boronate (0.647 g, 2.69 mmol) and

Pd(PPhî)4 (0.144 g, 0.124 mmol) in a mix of DME (15.0 mL) and 2.0 MNajCOj (1.27 mL).

The reaction is irradiated in MW at 120 °C for 40 min. It is concentrated under N2 and is purified by silica gel chromatography using a gradient of 12-100% EtOAc in heptanes. The desired fractions are concentrated to afford a white solid (0.662 g).

Substrate 21-5 (1.029 g, 3.58 mmol), NalO4 (2.34 g, 10.94 mmol), 2.5 wt % OsO₄ in r-BuOH (1.0 mL), THF (12.4 mL) and HiO (2.4 mL) are combined at room température, then stirred ovemight in the dark. The reaction mixture is diluted with water and dichlorométhane. The layers are separated with a hydrophobie frit. The organics are dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel chromatography using a gradient of 12-100%

EtOAc in heptanes to yield an amber oil (0.786 g).

Aldéhyde 21-6 (0.785 g, 2.71 mmol) is dissolved in THF (5.0 mL) and MeOH (5.0 mL). The mixture is cooled to 0 °C and NaBIL (0.156 g, 4.07 mmol) is added. The reaction is stirred at room température for 30 min. The reaction is quenched with aq. NH4CI and is stirred for 10 min.

!t is extracted with EtOAc, washed with NH4CI, brine, dried over MgSO4, and concentrated. The resultîng material is purified by silica gel chromatography using a gradient of 12-100% EtOAc in

104 heptanes. The desired fractions are collected to yield the desired product 21-7 (0.626 g) as a white solid.

To a solution of alcohol 21-7 (0.300 g, 1.030 mmol) and N,N-diisopropylethylamine (0.269 mL, 5 1.54 mmol) in dichloromethane (10.0 mL) is added triphenylphosphine dibromide (0.679 g, 1.54 mmol) at 0 °C. The reaction is stirred for 2 h and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using a gradient of 7-60% EtOAc in heptanes to yield the desired product 21-8 (0.338 g) as a white solid.

Sîmilarly, the following bromides were prepared from the appropriate starting materials as described in Example 21:

21-9

•ΤΟγ

The following compound from Table 1 is prepared according to the procedure described in 15 Example 7a, using phénol, 2-8, bromide, 21-8, and other appropriate starting materials and purification conditions:

Compound 120: MS, electrospray, m/z = 583.5 [M+H], RT 0.74 min;

Compound 178: MS, electrospray, m/z = 555.3 [M+H], RT 0.64 min (Method Bl).

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 21-8, and other appropriate starting materials and purification conditions:

Compound 132: MS, electrospray, m/z « 597.5 [M+H], RT 0.83 min.

105

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 21-9, and other appropriate starting materials and purification conditions:

Compound 154: MS, electrospray, m/z = 597.7 [M+H], RT 0.81 min.

Example 22. Préparation of Intermediates 5-Bromomethyl-4-methyl-l,3-dlhydrolsolndole-2-carboxylic acid tert-butyl ester (22-5) and 6-Bromomethyl-4-methyl-13dihydro-isolndole-2-carboxylic acid tert-butyl ester (22-6)

22-5 22-6

To a stirred solution of Boc-amine 22-1 (2.00 g, 12.89 mmol) in THF (30.0 mL) and tetrabutylammonium iodide (0.476 g, 1.29 mmol) is added 0.5 M KHMDS solution (25.8 mL) and the mixture is stirred for 30 min at room température. The bromide (1.69 mL, 19.33 mmol) is added dropwise and the mixture is stirred for 30 min at room température and then is refluxed for 2 h. The reaction is quenched with saturated NH4CI and extracted with EtOAc. The combined organics are dried with MgSÛ4 and concentrated in vacuo. The crude matériel is purified by silica gel chromatography using a gradient of 5-40% EtOAc in heptanes to yield the desired product (2.13 g) as a colorless oil.

Propargyl alcohol (2.39 mL, 41.11 mmol) is added dropwise at 0 °C to a solution of diacetylene 22-2 (2.13 g, 10.28 mmol) in anhydrous éthanol (50.0 mL). Wilkînson's catalyst (0.95 g, 1.028 mmol) is added to the mixture and it stirred ovemight at room température. The crade reaction is concentrated in vacuo and subjected to silica gel chromatography using a gradient of 10-80%

106

EtOAc in heptanes. The desired fractions are collected and concentrated to afford both regioisomers 22-3 and 22-4 (1.93 g). The mixture is carried on to the next step.

To a solution of the mixture of alcohols 22-3 and 22-4 (1.93 g, 7.33 mmol) and N,N5 diisopropylethylamine ( 1.91 mL, 10.98 mmol) in dichloromethane (50.0 mL) is added triphenylphosphine dibromide (4.73 g, 10.98 mmol) at 0 °C. The reaction is stirred for 2 h and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using a gradient of7-60% EtOAc in heptanes to yield the mixture of regioisomers 22-5 and 22-6 (2.12 g) as a white solid.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 22-5, and other appropriate starting materials and purification conditions:

Compound 256: MS, electrospray, m/z = 555.4 [M+H], RT 1,13 min (Method A2); Compound 257: MS, electrospray, m/z = 527.3 [M+H], RT 1.12 min (Method A2). The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 22-6, and other appropriate starting materials and purification conditions:

Compound 255: MS, electrospray, m/z = 555.4 [M+H], RT 1.15 min (Method A2); Compound 258: MS, electrospray, m/z = 527.3 [M+H], RT 1.16 min (Method A2).

Example 7a, using phénol, 3-15, bromide, 22-5. and other appropriate starting materials and purification conditions:

Compound 119: MS, electrospray, m/z = 569.3 [M+H], RT 1.13 min (Method A2);

107

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 22-6, and other appropriate starting matériels and purification conditions:

Compound 118: MS, electrospray, m/z = 569.3 [M+H], RT 1.11 min (Method A2);

Example 23. Préparation of intermedlate 5-Bromomethyl-6-methyl-l,3-dihydrolsolndoIe-2-carboxylIc acid tcrt-butyl ester (23-3).

23-1

Wilkinson's, EtOH

PPhjBrj, DIPEA

23-2

DCM

23-3

The alcohol (0.968 mL, 12.94 mmol) is added dropwise at 0 °C to a solution of diacetylene 23-1 (500 mg, 2.59 mmol) in anhydrous éthanol (12.0 mL). Wilkinson's catalyst (239.4 mg, 0.259 mmol) is added to the mixture and it stirred ovemight at room température. The crude reaction is concentrated in vacuo and subjected to silica gel chromatography using a gradient of 10-80% EtOAc in heptanes. The desired fractions are collected and concentrated yielding a solid (105 mg).

To a solution of alcohol 23-2 (105 mg, 0.399 mmol) and N,N-Diisopropylethylamine (0.104 mL, 0.598 mmol) in dichloromethane (7.0 mL) is added triphenylphosphine dibromide (263 mg, 0.598 mmol) at 0 °C. The reaction is stirred for 2 h and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using a gradient of 7-60% EtOAc in heptanes to yield 23-3.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 23-3, and other appropriate starting matériels and purification conditions:

108

Compound 143: MS, electrospray, m/z = 555.4 [M+H], RT 0.74 min.

Example 24: Préparation of 5-Ethoxy-l-(6-[3-methyi-2-[5-methyi-2-(tetrahydro-pyran-4carbonyl)-l,2,3,4-tetrahydro-isoquinolin-6-ylmethoxy]-phenyl}-pyridin-2-yi)-lH-pyrazole-

4-carboxyiic acid (Compound 147)

o

12-48 Compound 147

Amine 12-48 (122 mg, 0.232 mmol) is combined with DMAP (2 mg, 0.02 mmol) and DIPEA (60 pL, 0.34 mmol) in dichloromethane (5 mL) at rt. Tetrahydro-2H-pyran-4-carbonyl chloride (40 pL, 0.23 mmol) is added, and the mixture is stirred ovemight at rt. The mixture is applied directiy to a samplet, and then purified by elution with 100% dichloromethane on a 50g HP-Sil SNAP cartridge (Biotage). Concentration in vacuo affords the intermediate ester (31 mg) that is used immediately in the next step.

Ester (30 mg) is dissolved in EtOH/H₂O/THF (i, 0.5,0.5 mL) and treated with LiOH (26 mg, 1.2 mmol). The mixture is stirred at 45 °C o/n, and then concentrated under N₂. The residue is then purified by gradient elution (5-95% MeCN/water + 0.1% TFA) on a 12g KP-CI8 SNAP cartridge (Biotage). The product is concentrated in vacuo, to afford Compound 150 (26 mg).

Compound 147: MS, electrospray, m/z-611.3 [M+H], RT 1.04 min (Method Bl)

Example 25: Préparation of intermediate 6-Bromomethyl-8-methyl-3,4-dIhydro-lIIisoquinoline-2-carboxyiic acid tert-butyl ester (25-14)

109

CO. MeOH dppp

PPhjBr,

25-12

25-13

25-14

To a mixture of25-01 (185 g; 0.940 mol), K₂COj (437 g, 3.17 mol) in acetone (2 L) is added

Mel (424 g, 2.99 mol). The mixture is stirred at 40 °C for 16 h. After filtration, the mixture is purified by silica gel column (PE: EtOAc = 500: 1 ) to give l-Bromo-3-methoxy-5-methylbenzene, 25-02 (189 g) as a light yellow oil.

To a mixture of25-02 (200 g, 0.995 mol) in dry THF (1.70 L) is added dropwise n-BuLi (438 ml; 1.09 mol) at -70 °C. After stirring for I h at -70 °C, dry DMF (76.3 g, 1.04 mol) is added to dropwise at -70°C and stirred for 1 h at -70*C. The mixture is poured into NH4CI (1.00 L) and extracted with EtOAc (500 mL x 3), washed with brine (500 mL x 2), dried over Na₂SO4 and concentrated to give 3-Methoxy-5-methyl-benzaldehyde, 25-03 (147 g) as a yellow oil.

The mixture of25-03 (150 g, 0.999 mol) and NH4OAC (30.8 g, 0.40 mol) in MeNO₂ (1.5 L) is refluxed for 16 h. The mixture is concentrated, then diluted with EtOAc (1000 mL), washed with water ( 1 L), brine ( 100 mL), the organic layers are dried over Na₂SO4 and concentrated. The

110 mixture is triturated with PE: EtOAc = 10: 1 for 10 minutes, filtered to give l-Methoxy-3methyl-5-((E)-2-nitro-vinyl)-benzene, 25-04 (80 g) as yellow solid.

To a mixture of L1AIH4 (78.6 g, 2.00 mol) in dry THF (1 L) Îs added 25-04 (78 g, 0.404 mol) in portions at 0 *C in THF (200 mL) and stirred for 16 h at 70 *C. The mixture is cooled to 0 °C, quenched slowly with water (78 mL), 15% NaOH (78 mL) and water (235 mL). Aller filtration, the mixture is concentrated to give 2-(3-Methoxy-5-methyl-pheny!)-ethylamine, 25-05 (40 g) as a light yellow oil.

The mixture of compound 25-05 (66 g, 0.40 mol) and formic acid (73.5 g, 1.60 mol) in dioxane (600 mL) is stirred for 16 h at 90*C. The mixture was concentrated to give N-[2-(3-Methoxy-5methy!-phenyl)-ethyl]-formamide, 25-06 (77 g) as yellow solid.

To a solution of 25-06 (76.0 g, 0.354 mol) in dichloromethane (2.5 L) is added POCIj (155 g, 1.01 mol) at 15 ’C and refluxed for 3 h. The solution is concentrated, to the residue is added water ( 1.5 L), toluene ( 1.5 L) and 20% NaOH (500 mL), then refluxed for I h and cooled. The mixture is diluted with EtOAc (500 mL x 3), washed with water (1 L x 2), brine (100 mL x 2), the combined organics were dried over Na₂SO4 and concentrated. It is purified by silica gel column (PE: EtOAc = 10: I) to give 6-Methoxy-8-methyl-3,4-dihydro-isoquinoline, 25-07 (58.5 g) as brown oil.

To a solution of 25-07 (58.5 g, 0.334 mol) in MeOH (500 mL) is added NaBFL (63.3 g, 1.67 mol) at 0*C and the mixture is maintained at 0*C for 4 h. The solution is quenched with IN HCl (100 mL), pH is adjusted to 8 by addition of NaHCOj. extracted with dichloromethane (300 mL x 2), the combined organics are dried over Na₂SO4 and concentrated to aflord 6-Methoxy-8methy!-3,4-dihydro-isoquinoline, 25-08 (83 g, crude) as brown oil.

A solution of crude 25-08 (83 g, 0.47 mol) in HBr (40% in water, 500 mL) is heated to 90 ’C for 12 h. The solution is evaporated under reduced pressure to obtain 8-Methyl-l,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide, 25-09. To this crude residue is added BocjO (72 g, 0.33 mol) and triethylamine (63 g, 0.62 mol) and the resulting mixture is stirred for 12 h at 15 *C, then diluted

111 with dichloromethane (1500 mL) and water (100 mL). The organics layer is washed with 0.5 N HCl (100 mL) and brine (100 mL), dried, concentrated, and purified by silica gel column (PE: EtOAc = 30: 1) to give 6-Hydroxy-8-methyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tertbutyl ester, 25-10 (33.4 g) as a white solid.

To a solution of25-10 (33 g; 0.113 mol) and pyridine (20.1 g, 0.254 mol) in dry dichloromethane (300 mL) is added Tf₂O (39.4 g, 0.139 mol) drop-wise at -30°C and stirred for 1 h at -30°C. Then the solution is warmed toi5’C and stirred for 8 h. The mixture is diluted with dichloromethane (500 mL) and water (100 mL), and the combined organics are concentrated and then purified by silica gel column (PE: EtOAc “50: 1) to give 8-Methyl-6trifluoromethanesulfonyloxy-3,4-dihydro-IH-isoquinoline-2-carboxylic acid tert-butyl ester, 2511 (43 g) as a white solid.

A solution of 25-11 (43 g, 0.109 mol), EtjN (33.0 g, 0.327 mol), DPPP (4.53 g) and Pd(OAc)₂ (5 g) in MeOH (500 mL) is stirred under 3 MPa pressure of CO at 90 °C for 2 days. After filtration and concentration the residue is purified by silica gel chromatography (PE: EtOAc =50: 1) to afiord 8-Methyl-3,4-dihydro-lH-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 6-meihyl ester, 25-12 (21 g) as a colorless oil.

To a solution of 25-12 (21 g, 0.693 mol) in dry THF (500 mL) is added LiAlH4(7.4 g, 208 mmol) at -50’C. The mixture is stirred at -50°C for I h, and then 0°C for 30 min. The reaction is slowly quenched with H₂O (7.4 mL), 15% NaOH (7.4 mL), and H₂O (22.2 mL) and then filtered. The Hltrate is concentrated and purified by prep-HPLC and concentrated. The residue is extracted with dichloromethane (1 L x 2), the combined organics were dried over Na₂SC>4 and concentrated to give 6-Hydroxymethyl-8-methyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester, 25-13 (14.8 g) as a colorless oil.

To a solution of 25-13 (13.4 g, 0.485 mol) and D1EA (11.8 mL, 0.679 mol) in dichloromethane (200 mL) at -30 °C is added triphenylphosphine dibromide (26.6 g, 0.606 mol). The resulting mixture was stirred I h, over which time cold bath is allowed to warm to -10 °C. Volatiles are stripped from the -10 °C mixture, the residue is suspended in dichloromethane (50 mL), and the

112 filtrate is purified by chromatography (silica gel, 5-40% EtOAc in heptane) to provide the desired intermediate 25-14 (16.2 g) as a white solid.

Similarly, the following bromides were prepared from the appropriate starting materials as described in Example 25:

25-15
	Ύ

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 1-6, bromide, 25-14, and other appropriate starting materials and purification conditions:

Compound 161: MS, electrospray, m/z = 597.3 [M+H], RT 0.75 min.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 25-14, and other appropriate starting materials and purification conditions:

Compound 171: MS, electrospray, m/z · 569.3 [M+H], RT 0.68 min;

Compound 186: MS, electrospray, m/z = 541.3 [M+H], RT 0.60 min;

Compound 237: MS, electrospray, m/z = 569.3 [M+H], RT 0.60 min;

Compound 239: MS, electrospray, m/z = 569.3 [M+H], RT 0.60 min;

Compound 240: MS, electrospray, m/z = 585.2 [M+H], RT 0.60 min;

Compound 242: MS, electrospray, m/z = 555.3 [M+H], RT 0.59 min;

Compound 244: MS, electrospray, m/z = 557.3 [M+H], RT 0.62 min.

113

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 25-14, and other appropriate starting materials and purification conditions:

Compound 169: MS, electrospray, m/z = 583.3 [M+H], RT 0.73 min;

Compound 173: MS, electrospray, m/z *= 583.3 [M+H], RT 0.74 min;

Compound 174: MS, electrospray, m/z = 555.3 [M+H], RT 0.72 min;

Compound 195: MS, electrospray, m/z = 583.4 [M+H], RT 0.71 min;

Resolution: IC column 15% l:l:lMeOH:EtOH:iPA + diethylamine:CO2,3 ml/min, 40°C, 10 200bar

Compound 197: MS, electrospray, m/z = 583.4 [M+H], RT 0.71 min;

Resolution: IC column 15% l:l:lMeOH:EtOH:iPA + diethylamine:CO2,3 ml/min, 40°C, 200bar

Compound 200: MS, electrospray, m/z = 583.3 [M+H], RT 0.63 min (Method B1);

Compound 210: MS, electrospray, m/z = 571.1 [M+H], RT0.70 min (Method Bl);

Compound 241: MS, electrospray, m/z = 569.3 [M+H], RT 0.62 min;

Compound 243: MS, electrospray, m/z = 599.3 [M+H], RT 0.63 min;

Example 7a, using phénol, 2-8, bromide, 25-15, and other appropriate starting materials and purification conditions:

Compound 121: MS, electrospray, m/z = 569.4 [M+H], RT 0.72 min.

Example 26; Préparation of Intermediate 6-Bromomethyl-8-methyl-3,4-dihydro-lIIlsoqulnollne-2-carboxylic acid tert-butyl ester (26-12).

114

A round-bottom llask is charged with 2-Hydroxy-4-iodo-benzoic acid methyl ester, 26-01 (12.0 g, 43.2 mmol), 2,4,6-TrivÎnyl-cyclotriboroxane-pyridine complex (11.4 g, 47.5 mmol), tetrakis(triphenylphosphine) palladium (2.49 g, 2.16 mmol), 2.0 M aqueous solution of sodium carbonate (25.9 mL, 51.7 mmol), and 1,2-dimethoxyethane (50 mL), deoxygenated by altemating between vacuum and argon (3x), and refluxed under argon pressure for 3 h, and then stirred 18 h at ambient température. Volïtiles are stripped in vacuo, the residue is suspended in IN HCl (800 mL) and extracted with EtOAc (600 mL, 300 mL, and then 300 mL). The combined organic extracts are washed brine, dried over NaSCh, and purified by chromatography (silica gel, 5-30% EtOAc in heptane) to afford 2-Hydroxy-4-vinyl-benzoic acid, 26-02 (3.70 g) and 2-Hydroxy-4-vinyl-benzoic acid methyl ester (0.300 g).

115

To a solution of26-02 (3.70 g, 22.0 mmol) and 2-Hydroxy-4-vinyl-benzoic acid methyl ester (0.300 g, 1.69 mmol) in MeOH (50 mL) is added H2SO4 (4.0 mL, 75 mmol). The resulting mixture is refluxed for 16 h and then allowed to cool to room température. ïce (100 g) is added and the mixture is stirred. When the ice completely melts, the MeOH is removed under reduced pressure and the aqueous residue is extracted with DCM (2x 100 mL). The combined organic extracts are combined, concentrated in vacuo and purified by chromatography (silica gel, 0-5% EtOAc in heptane) to give 2-Hydroxy-4-vinyl-benzoic acid methyl ester, 26-03 (3.75 g) as a clear oil.

To a stirring mixture of 26-03 (3.75 g, 21 mmol) and Sodium metaperiodate ( 13.8 g, 64.3 mmol) in THF (80 mL) and water (20 mL) is added a 4 wt% solution of osmium tetraoxide in water (3.69 mL, 0.47 mmol). The reaction flask (which warms upon addition of the osmium reagent) is wrapped in aluminum foîl to shîeld contents from light, and the slurry is stirred 16 h. Volitiles are removed under reduced pressure, the residue is diluted with saturated aqueous NaHCO3 (700 mL) and extracted with EtOAc (700 mL, 200 mL, and then 200 mL). Combined organic extracts are concentrated in vacuo and then purified by chromatography (silica gel, 0-50% EtOAc in heptane) to afford 4-Formyl-2-hydroxy-benzoic acid methyl ester, 26-04 (2.25 g) as a yellow solid.

In a round-bottom flask with Dean Stark trap attached, 26-04 (2.25g, 12 mmol) and aminoacetaldehyde dimethyl acetal (1.31 g, 12 mmol) are refluxed in toluene 3 h. Reaction mixture is concentrated in vacuo to afford crude 4-{[2,2-Dimethoxy-ethylimino]-methyl}-2hydroxy-benzoic acid methyl ester, 26-05 (3.33 g, 12.4 mmol) as a brown oil. To this crude oil is added a large stir bar, polyphosphoric acid (25.0 g), and phosphorous pentoxide (33.0 g, 232 mmol). The resulting, viscous tar îs stirred at 80 °C for 5 h. The reaction mixture is diluted with H₂O (600 mL), transfened to a 5 L Erlenmyer flask, and the vigerously stirred mixture is carefully treated with small portions of solid NaHCO3 until said addition no longer cause receiving mixture to foam. Basic aqueous mixture is then extracted with DCM (5 x 200 mL). The combined organic extracts are washed with H₂O (2 x 50 mL), dried with Na2SO4, concentrated under vacuo and then purified by choratography (silica gel, 0-100% EtOAc in heptane) to yield

5-Hydroxy-isoquinoline-6-carboxylic acid methyl ester, 26-06 (0.520 g).

116

26-06 (0.520 g, 2.46 mmol) is dissolved in MeOH (15 mL) and then 4N HCl in dioxane (6.15 mL, 24 mmol) is added. Hydrogenated on an H-Cube apparatus by continuously cycling solution through a PtO₂ cartridge al a rate of ImL / minute under 10 mbar of H₂-pressure for 5 h, then under 50 mbar Hî-pressure for 15 h. Reaction mixture is concentrated under reduced pressure to get crude 5-Hydroxy-l,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methyl ester; hydrochloride, 26-07 (0.90 g) as a red solid. This crude solid is dissolved in DCM (30 mL) and cooled to 0 °C before adding triethylamine ( 1.65 mL, 11 mmol) and then di-tert-butyl dicarbonate (1.70 mL, 7.39 mmol). Reaction mixture is removed from cold bath, stirred 16 h, concentrated under reduced pressure and purified by chromatography (silica gel, 0-50% EtOAc inheptane). Desired intermediate 5-Hydroxy-3,4-dihydro-lH-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 6-methyl ester 26-08 (0.492 g) co-elutes with di-tert-butyl dicarbonate (1.61g). The mixture (2.1 g) is dissolved in MeOH (50 mL), K₂COj (2.21 g, 16 mmol) is added and the resulting mixture is stirred 16 h. Supematant is removed from reaction flask and sédiment is triturated with MeOH (2 x 10 mL). The combined methanolic supematants are concentrated under reduced pressure, dissolved in EtOAc (50 mL), washed with IN HCl (3 x 30 mL), brine (10 mL), dried with Na2SO4, and concentrated in vacuo to get 26-08 (0.422g). This residue is combined with iodomethane (1.0 mL, 16 mmol), K₂COj (0.20 g, 1.5 mmol), Cs₂CO₂ (0.40 g, 1.5 mmol), and acetone (4.0 mL) and irradiated in microwave at 70 °C for 7 h. Mixture is concentrated under reduced pressure and purified by chromatography (silica gel, 0-100% EtOAc) to afford impure 5-Methoxy-3,4-dihydro-lH-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester

6-methyl ester, 26-09 (0.245 g) which was carried forward as is.

Impure 26-09 (0.240 g, 0.51 mmol) is combined with lithium hydroxide ( 1.22 g, 5.1 mmol) in THF (4.0 mL), MeOH (4.0 mL) and water (2.0 mL). The mixture is heated 45 minutes at 55 °C and then concentrated under reduced pressure. The residue is dissolved in EtOAc (20 mL), washed with IN HCl (3 x 50mL), brine (10 mL), dried with NaîSOi, and concentrated in vacuo to give crude 5-Methoxy-3,4-dihydro-lH-isoquinoline-2,6-dicafboxylic acid 2-tert-butyl ester, 26-10 (0.177 g) as a white solid.

117

To a solution ofcrude 26-10 (0.177 g, 0.58 mmol) in THF (3 mL) is added a IM borane in THF solution (1.27 mL, 1.27 mmol) and the resulting mixture is stirred for 18 h. Reaction mixture is concentrated in vacuo and purified by reverse-phase chromatography (Cl8 silica gel, 5-95 % MeCN, in H2O with 0.1 % TFA) to get 6-Hydroxymethyl-5-methoxy-3,4-dihydro-l H5 isoquinoline-2-carboxylic acid tert-butyl ester, 26-11 (0.125 g) as a clear, colorless residue.

26-11 (0.125 g, 0.43 mmol) and N,N-diisopropylethylamine (0.111 mL, 0.64 mmol) are dissolved in DCM (4.0 mL), the resulting mixture is deoxygenated by altemating between argon and vacuum (3x), and then cooled to -30 °C. Triphenylphosphine dibromide (0.262 g, 0.60 mmol) is added and the resulting mixture stirs for 3 h as cold bath warms to - 15 °C. Reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography (silica gel, 5-50% EtOAc in heptane) to afford desired intermediate 6-Bromomethyl-5-methoxy-

3.4- dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester, 26-12 (0.103 g).

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 3-15, bromide, 26-12, and other appropriate starting materials and purification conditions:

Compound 220: MS, electrospray, m/z = 599.3 [M+H], RT 0.71 min;

Compound 221: MS, electrospray, m/z = 571.3 [M+H], RT 0.71 min;

Example 27: 5-Methoxy-l-(6-{3-methyl-2-[5-methyl-l-oxo-2-(tetrahydro-pyran-4-yI)-

1.23.4- tetrahydro-lsoqulnolln-6-ylmethoxy[-phenyl]-pyrldIn-2-yl)-lH-pyrazoIe-4carboxyllc acid

118

Compound 167

To a suspension of compound 27 (0.065 g, 0.11 mmol) in a 4:1 mixture of 1,1,2,2,tetrachloroethane:water (1.2 mL) is added sodium chlorite (0.035 g, 0.39 mmol). The mixture was heated at 55°C for 2 hours then cooled to room température and the mixture purified by C18 flash reverse phase chromatography to aflord the tîtle compound (0.009 g).

Compound 167; MS, electrospray, m/z = 584.8 [M+H], RT 1.01 min.

The following compound is prepared according to the above procedure using Compound 114 as the appropriate starting materials and purification conditions:

Compound 194: MS, electrospray, m/z = 597.22 [M+H], RT 1.02 min.

Example 28: Préparation of l-[6-|2-(2-(S)-l-[l,4]Dioxan-2-ylmethyl-5-methyl-l,23»415 tetrahydro-isoqulnolin-6-ylmethoxy)-3-methyl-phenyl]-pyrldln-2-yl}-5-ethoxy-lHpyrazole-4-carboxyllc acid

119

8-42

28-1

Amine 8-42 (80.0 mg, 0.152 mmol) is dissolved in acetonitrile (3.0 mL) and chloride (16.87 mg, 0.182 mmol) and Cs₂COj (51.5 mg, 0.243 mmol) are added. The reaction is heated to 60 °C and stirred ovemight. LC-MS indicated the desired mass. The reaction is extracted with EtOAc, washed with brine, dried over MgSO₄, and concentrated. The resulting residue is subjected to silica gel chromatography using a gradient of 12-100% EtOAc in heptanes. The desired fractions are collected and concentrated to yield the product (43.0 mg).

To a solution of epoxide 28-1 (43.0 mg, 0.074 mmol) and DCE (2.0 mL) is added 2chloroethanol (0.005 mL, 0.081 mmol) followed by a solution of BFjEt₂O (0.01 mL) in DCE. The reaction is stirred at 45 °C ovemight. The reaction mixture is cooled to room température and is concentrated. The resulting matériel is carried on crude to the next step.

To starting matériel 28-2 (40.0 mg) is added a solution of 2.0 M NaOH (2.0 mL). This solution is heated to 90°C and becomes homogeneous. It is stirred for 3 h and the reaction is cooled to room température. It is subjected to a CI8 column (20-80% ACN in Water with 0.1% TFA). The desired fractions were collected and concentrated to yield the desired compound 18 (19.1 mg).

Compound 185: MS, electrospray, m/z = 599.3 [M+H], RT 0.75 min, Method Bl.

The following compound is prepared according to the procedure described in Example 28, using the appropriate starting materials and purification conditions:

Compound 170: MS, electrospray, m/z « 599.3 [M+H], RT 0.63 min, Method Bl.

120

Example 29: tert-Butyl 8-ethyl-6(hydroxymethyl)-3,4-dlhydroisoquinoline-2(lfl) carboxylate (29-13)

29*1

I^COy Mal, DUjF rt.24

29-2

MeO

R3 --—----►

CCI₄, reflux, ovemight

Br

29-3

TBAF, TMSCN --------->CHjCN, r.t ovemight

Br

29-4

NI. 30 Psi. H2. HCHO, HCOOH

NH3.H2O [I j ' ________________

MeOH.r.t.. 5h ^NHj 50°C, ovemight

Br

29-6

HBraq.

90°C, 12 h

29Βοο,Ο, EtjN ------->THF, H2O r.t. 3 h

'B oc

29-8

29-7

Pd(dppf)CI2, K2CO3 Pd(PPh3)4. DMF reflux, ovemight

29-9

29-10

Tf20, Et3N

---->

DCM, r.t., 3 h

29-11

Pd(OAc)_;. TEA_

DPPP, MeOH CO, 3 MPa 90 «C, 2d

To the mixture of compound 29-1 (300 g, 1.6 mol) and K₂COj (665 g, 4.8 mol) in DMF (2000 mL) was added Mel(250 g, 1.8 moi) dropwised at room température. The mixture was stirred ovemight. TLC showed the reaction is completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dired, fîltered, evaporated under reduced pressure

121 to give the crude product which was purified by chromatography on silica gel to gîve compound 29-2 (165 g, 52% yield).

The solution of compound 29-2 (100 g, 497.4 mmol), NBS (88.5 g, 497.4 mmol) and A1BN (10 g, 10%) in CCh (700 mL) was heated to reflux for 12 h. TLC showed the reaction is completed. Aller cooling down to room température, the reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 29-3 (48 g, 42% yield).

The solution of compound 29-3 (80 g, 285.7 mmol) and TMSCN (28.2 g, 285.7 mmol) in ACN (600 ml) was stirred at room température for 0.5 h. TBAF (74.6 g, 285.7 mmol) was added into the reaction mixture at ice based and the mixture was stirred for 12 h. TLC showed the reaction was completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 29-4 (39 g, 60% yield).

The solution of compound 29-4 (12 g, 53.1 mmol) and Ni (10 g) in MeOH (80 ml) and NHj.H₂O (80 ml) was stirred under H₂ whith a pressure of 50 psi at room température for 5 h. TLC showed the reaction was completed. The mixture was filtered and the filtrate was concentrate on vacuum 20 pump to give the crude product (8 g) which was used directly in the next step.

The solution of compound 29-5 (75 g, 326.08 mmol) and HCHO (8.8 g, 293.47 mmol) in HCO₂H (500 ml) was stirred at 50 °C under N₂ ovemight. LCMS showed the reaction was completed. The solvent was removed under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 29-6 (54 g, 64% yield for 2 steps).

The solution of compound 29-6 (45 g, 186 mmol) in aqueous HBr solution (400 ml) was stirred at 90 °C for 12 h. LCMS showed the reaction was completed. The solvent was removed under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 29-7 (20.75 g, 53% yield).

122

The solution of compound 29-7 (20 g, 87.7 mmol), Boc₂O (19.1 g, 87.7 mmol) and TEA (17.7 g,

175.4 mmol) in THF/H₂O (1:1) (200 ml) was stirred at room température for 3 h. TLC showed the reaction is completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product 5 which was purified by chromatography on silica gel to give compound 29-8 (20 g, 70% yield).

The solution of compound 29-8 (14 g, 42.7 mmol), K₂COj (17.66 g, 128 mmol), Pd(dppf)CI₂(2.5 g), Pd (PPhj)₄ (2.5 g), and compound 29-8B (7.22 g, 46.9 mmol) in DMF (150 ml) was stirred at reflux ovemight. TLC showed the reaction is completed. After filtration, the filtrate tO was concentrate under reduced pressure and the residue was purified by chromatography on silica gel to give compound 29-9 (7.2 g, 61% yield).

The solution of compound 29-9 (7.2 g, 26.2 mmol) and Pd-C (2 g) in MeOH (100 ml) was stirred under H₂ with a pressure of 50 psi at room température for 12 h. TLC showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to give crude product which was purified by chromatography on silica gel to give compound 29-10 (5.8g, 80% yield).

The solution of compound 29-10 (5.8 g, 20.9 mmol), Tf₂O (5.9 g, 20.9 mmol) and TEA (6.3 g, 62.7 mmol) in DCM (70 ml) was stirred at room température for 3 h. TLC showed the reaction was completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 29-11 (7 g, 82% yield).

A mixture ofcompound 29-11 (7 g, 17.1 mmol), Pd(OAc)₂ (1.4 g), dppp (1.4 g) and EtjN (5.2 g, 25 51.3 mmol) in MeOH (80 mL) was stirred at 80 °C under CO with a pressure of 3 MPa for 2 d.

The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give compound 29-12 (4.8 g, 88% yield).

To a solution of L1AIH4 (1.1 g, 30.1 mmol) in THF (10 mL) was added dropwise the solution of 30 compound 29-12 (4.8 g, 15.0 mmol) in THF (50 mL) at -50 °C over 30 min. After addition, the reaction mixture was stirred at 0 °C for 2.5 h. Then the reaction mixture was treated with H₂O and DCM. The organic layer was separated, washed with brine, dried over Na₂SO₄, filtered and

123 concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give 29-13 (4.1 g, 92% yield).

Similarly, the bromide was prepared from 29-13 as described in Example 25 producing compound 29-14.

The following compound from Table 1 is prepared according to the procedure described in Example 7a, using phénol, 2-8, bromide, 29-14, and other appropriate starting matériels and purification conditions:

tû

Compound 248: MS, electrospray, m/z « 583.3 [M+H], RT 1.29 min (Method A2); Compound 249: MS, electrospray, m/z = 555.3 [M+H], RT 1.37 min (Method A2).

Example 30: tert-Butyl 8-cyano-6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(lZ7)15 carboxylate (30-12)

KjCO,. Met. DMF

304

NI, 30 Pii, Hj. ΝΗ,Η/3

30-2

NB3, ΛΙΒΝ _rCCI*, reflux, ovemight

TBAF, TMSCN

CHjCN.rt, ovemight

30-3

HBreq

80°C, 12h

30-4

BoCjO, El,N

30-4 rl,24 h tep 1,62% yield

MeOH.rl.5h

HCHO, HCOOH

50“C, ovemight

Hep 6

30-a

THF. H₂O fl3h

304

Pd(PPhi),, DMF 120 *C. ovemight

ZnCW, Zn, Pd(dppf)Cÿ

TTjO, TEA

DCM, rt.Sh

Pd(OAc);,TEA

DPPP. MeOH CO, 3 MP* 00 °C, 2d

30-10

30-a

124

To the mixture of compound 30-1 (300 g, 1.6 mol) and K2CO3 (665 g, 4.8 mol) in DMF (2000 mL) was added Meï(25O g, 1.8 mol) dropwised at room température. The mixture was stirred ovemight. TLC showed the reaction is completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dired, filtered, evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to gîve compound 30-2 (165 g, 52% yield).

The solution of compound 30-2 (100 g, 497.4 mmol), NBS (88.5 g, 497.4 mmol) and AIBN (10 g, 10%) in CCI4 (700 mL) was heated to reflux for 12 h. TLC showed the reaction is completed.

Aller cooling down to room température, the reaction was quenched by H2O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 30-3 (48 g, 42% yield).

The solution of compound 30-3 (80 g, 285.7 mmol) and TMSCN (28.2 g, 285.7 mmol) in ACN (600 ml) was stirred at room température for 0.5 h. TBAF (74.6 g, 285.7 mmol) was added into the reaction mixture at ice based and the mixture was stirred for 12 h. TLC showed the reaction was completed. The reaction was quenched by H2O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 30-4 (39 g, 60% yield).

The solution of compound 30-4 (12 g, 53.1 mmol) and Ni (10 g) in MeOH (80 ml) and NH3.H2O (80 ml) was stirred under H₂ whith a pressure of 50 psi at room température for 5 h. TLC showed the reaction was completed. The mixture was filtered and the filtrate was concentrate on vacuum pump to give the crude product (8 g) which was used directly in the next step.

The solution of compound 30-5 (75 g, 326.08 mmol) and HCHO (8.8 g, 293.47 mmol) in HCO₂H (500 ml) was stirred at 50 °C under N₂ ovemight. LCMS showed the reaction was completed. The solvent was removed under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 30-6 (54 g, 64% yield for 2 steps).

125

The solution of compound 30-6 (45 g, 186 mmol) in aqueous HBr solution (400 ml) was stirred at 90 °C for 12 h. LCMS showed the reaction was completed. The solvent was removed under reduced pressure to gîve the crude product which was purified by chromatography on silica gel to give compound 30-7 (20.75 g, 53% yield).

The solution of compound 30-7 (20 g, 87.7 mmol), Boc₂0 (19.1 g, 87.7 mmol) and TEA (17.7 g,

175.4 mmol) in THF/H₂O (1:1) (200 ml) was stirred at room température for 3 h. TLC showed the reaction is completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product 10 which was purified by chromatography on silica gel to give compound 30-8 (20 g, 70% yield).

A solution of compound 30-8 (11 g, 34.8 mmol), Pd(dppf)CI₂ (2.5 g), Pd (PPhj)^ (2.5 g), ZnCN (2.8 g, 31.3 mmol), Zn (1.1 g, 17.4 mmol) in DMF (110 ml) was stirred at reflux ovemight. TLC showed the reaction was completed. After filtration, the filtrate was concentrate under reduced t5 pressure and the residue was purified by chromatography on silica gel to give compound 30-9 (6.5 g, 71% yield).

The solution ofcompound 30-9 (12 g, 43.7 mmol), Tf₂O (12.3 g, 43.7 mmol) and TEA (13.3 g, 131.23mmol) in DCM (120 ml) was stirred at room température for 3 h. TLC showed the reaction was completed. The reaction was quenched by H₂O and extracted with EtOAc. The organic layer was dried, filtered and evaporated under reduced pressure to give the crude product which was purified by chromatography on silica gel to give compound 30-10 (9 g, 51% yield).

A mixture of compound 30-10 (9.5 g, 23.4 mmol), Pd(OAc)₂ (1.9 g), dppp (1.9 g) and EtjN (7.1 25 g, 70.1 mmol) in MeOH (90 mL) was stirred at 80 °C under CO with a pressure of 3 MPa for 2 d.

The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give compound 30-11 (6 g, 80% yield).

To a solution of L1AIH4 (1.4 g, 37.9 mmol) in THF (10 mL) was added dropwise the solution of 30 compound 30-11 (6 g, 19.0 mmol) in THF (50 mL) at -50 °C over 30 min. After addition, the reaction mixture was stirred at -20 °C for 4.5 h. Then the reaction mixture was treated with H₂O and DCM. The organic layer was separated, washed with brine, dried over Na₂SO4, filtered and

126 concentraled under reduced pressure. The residue was purified by chromatography on silica gel lo give 30-12 (4.1 g, 74% yield).

Similarly, the bromide was prepared from 30-12 as described in Example 25 producing compound 30-13.

The following compound from Table 1 is prepared according to lhe procedure described in Example 7a, using phénol, 2-8, bromide, 30-13, and other appropriate slarting maierials and purification conditions:

Compound 250: MS, electrospray, m/z = 580.2 [M+H], RT 0.61 min.

ASSESSMENT OF B1OLOG1CAL ACT1V1TY

Cellular Assav

The sGC cellular activator assay is performed in the presence and absence of 50% human sérum (HS) using Chinese hamster ovary cells that hâve been slably transfecled lo express lhe human 20 soluble guanylale cyclase alpha 1 and beta 1 subunits (sGC). Cells are preincubaled wilh 40 microM lH-[l,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ), an sGC inhibilor, for one h in bufler containing 0.1% bovine sérum albumin and 3-isobutyl-l-methylxanlhine (1BMX). Concentration response curves are prepared for lest compounds in DMSO. An intermédiare dilulion of the compounds is performed in either bufler containing IBMX or type AB HS 25 containing IBMX. Diluled compounds are added to cells and they are incubaled at room température for lhirty min. cGMP is measured using a CisBio homogeneous time resolved fluorescence kit and the EC50 is calculated for each compound.

Représentative compounds of the présent invention were tesled for aclivily the above assay. 30 Preferred compounds hâve an EC50 of <1,000 nM in the above assay and more preferred

127 compounds hâve an EC$o < 200 nM. As exemples, data for représentative compounds from Table 1 are shown in Table 2.

Table 2

Compound	ECso	Compound	ECso
Number	(nM)	Number	(nM)
1	39	130	21
2	11	131	410
3	29	132	11
4	11	133	27
5	9.	134	46
6	87	135	54
7	32	136	81
8	42	137	89
9	59	138	54
10	16	139	8.4
11	17	140	15
12	26	141	17
13	180	142	62
14	18	143	160
15	28	144	460
16	23	145	13
17	18	146	23
18	8	147	450
19	17	148	43
20	24	149	44
21	17	150	91
22	14	151	130

128

23	52	152	14
24	54	153	26
25	16	154	28
26	5	155	86
27	14	156	720
28	13	157	25
29	3.5	158	30
30	10	159	53
31	19	160	110
32	170	161	14
33	97	162	23
34	65	163	55
35	29	164	32
36	27	165	11
37	120	166	6.6
38	66	167	30
39	17	168	580
40	62	169	13
41	27	170	28
42	24	171	16
43	130	172	50
44	44	173	13
45	26	174	14
46	38	175	40
47	22	176	9.7
48	10	177	35
49	54	178	14
50	990	179	59
51	72	180	28
52	170	181	62

129

53	110	182	370
54	110	183	980
55	110	184	12
56	820	185	30
57	24	186	16
58	82	187	14
59	31	188	8.6
60	—	189	12
61	59	190	23
62	24	191	3.3
63	82	192	10
64	71	193	12
65	56	194	87
66	110	195	4.7
67	320	196	13
68	38	197	19
69	61	198	5.3
70	180	199	9
71	67	200	20
72	17	201	12
73	250	202	12
74	73	203	4.4
75	23	204	4.5
76	160	205	13
77	31	206	7.4
78	48	207	9.2
79	33	208	20
80	45	209	200
81	410	210	19
82	8	211	30

130

83	29	212	36
84	9	213	39
85	22	214	30
86	41	215	37
87	55	216	110
88	28	217	35
89	150	218	62
90	69	219	140
91	75	220	150
92	20	221	210
93	37	222	5.4
94	45	223	8.5
95	54	224	79
96	24	225	10
97	67	226	12
98	270	227	13
99	160	228	14
100	170	229	3.9
101	110	230	13
102	110	231	4.6
103	110	232	9.5
104	31	233	11
105	17	234	13
106	27	235	20
107	23	236	28
108	24	237	4.9
109	34	238	5.1
110	45	239	6.5
111	99	240	7.9
112	110	241	8

131

113	24	242	11
114	40	243	16
115	68	244	23
116	28	245	280
117	29	246	6.5
118	39	247	8.6
119	57	248	4.2
120	12	249	4.6
121	40	250	44
122	23	251	7
123	55	252	10
124	47	253	13
125	27	254	25
126	58	255	9.5
127	7.5	256	14
128	15	257	14
129	17	258	15

ASSESSMENT OF SOLUBILITY

Solubility is measured by the following method.

1. Sample préparation:

100 uL, 10 mM DMSO stock solution of each compound is prepared in a 96 weli plate format.

The experiment is done in single détermination at 3 pH values (2.2,4.5 and 6.8). For each pH and one reference, 40 uL of each compound is needed.

Buffer préparation:

132

Mcllvaine pH 2.2: To 2.076 g citric acid monohydrate and 0.043 g NajHPCh x 2H2O add 100 ml deionized water

Mcllvaine pH 4.5: To 1.166 g citric acid monohydrate and 1.585 g Νβ2ΗΡΟί x 2H2O add 100 ml deionized water

Mcllvaine pH 6.8: To 0.476 g citric acid monohydrate and 2.753 g Na2HPOi x 2H2O add 100 ml deionized water

With a suitable liquid handling device (Multipette® or a liquid handler) 390 uL of each bufler solution and 10 uL of compound is added to each well of a 96 deep well plate. The plates are covered fïrmly and shaken for 24 h on an over head shaker (at 54 RPM) at room température. The DMSO content in the final bufter is 2.5% v/v.

After 24 h the plates are centrifuged to remove droplets on the lid before opening (for —5 min at 2500 RPM).

The filtration is done under vacuum with Millipore 96 well filter plate. Filtrate is collected in a deep well plate and transferred to a suitable plate for UPLC analysis.

The référencé plate is prepared by adding 10 uL of compound to 390 uL of 50:50 acetonitrile/water in a 96 deep well plate and transferred to a suitable plate for UPLC analysis. Wells are checked visually for précipitation, any presence noted under commenta in reported results.

2. Sample measurement

The samples are measured with UPLC-UV using the chromatographie method described below.

stationary phase

Waters ACQUITY UPLC® BEH C18 1.7 pm

133

	2.5x50 mm
mobile phase
solvent A	0.I % formic acid (pH 3)
solvent B	acetonitrile with 0.I % formic acid

Gradient
0 min	5%B
I.O min	95 % B
I.3 min	95 % B
1.4 min	5%B
I.7 min	5%B

column température	40°C
Flow	0.8 mL/min
duration/cycle time	I.7 mîn/2.7 min
injection volume	2 pL
sample température	20 °C

PDA détection	Enable3D data
wavelength	254 nm
sampling rate	40 points/sec
resolution	4.8 nm

Waters Empower®2 software is used for generating Sample Sets (according to the plate layout), Sample Set Methods and Instrument Methods.

One Sample Set comprises the methods for three 96 well plates (one référencé plate and two sample plates, and includes one Sample Set Method and one Instrument Method).

134

3. Data Processing and Analysis

The UV chromatograms collected at 254 nm are integrated and processed.

It is assumed that the compound is completely dissolved in the référencé solution (50:50 acetonitrile/water)

Solubility data (pg/mL) for compounds from Table 1 is shown in Table 3 below.

to

Table 3

Compound Number	(pli 2.2)	(pli 4.5)	(pli 6.8)
1	95	80	87
2	110	83	88
3	96	79	81
4	100	81	83
5	98	76	72
6	90	64	81
7	110	77	91
8	110	82	98
9	94	70	82
10	94	50	73
11	23	<0.1	80
12	110	90	92
13	100	84	87
14	110	82	76
15	110	88	90
16	95	71	81
17	97	62	85

135

18	110	86	90
19	96	70	75
20	95	72	68
21	96	62	60
22	97	68	73
23	99	79	82
24	95	76	76
25	91	38	39
26	100	80	80
27	110	88	90
28	110	83	90
29	110	79	78
30	100	81	75
31	110	89	94
32	91	73	78
33	93	73	75
34	82	65	68
35	93	73	78
36	91	72	74
37	92	74	78
38	110	94	88
39	93	44	81
40	99	81	85
41	96	75	80
42	93	75	78
43	95	79	82
44	100	85	88
45	82	61	73
46	100	82	86
47	87	69	79

136

48	100	82	86
49	92	69	58
50	120	79	75
51	110	83	93
52	83	58	73
53	84	65	70
54	100	78	75
55	98	48	49
56	87	66	77
57	95	47	51
58	111	85	89
59	—	—	--
60	117	96	100
61	130	110	99
62	110	88	91
63	110	90	92
64	100	66	66
65	110	84	74
66	63	54	55
67	90	76	78
68	85	71	74
69	91	77	80
70	86	57	64
71	94	75	78
72	44	46	67
73	86	67	71
74	110	83	95
75	120	93	90
76	100	86	89
77	96	83	87

137

78	100	86	89
79	100	87	89
80	110	94	95
81	100	84	79
82	120	100	97
83	110	88	95
84	110	86	89
85	120	96	110
86	110	90	91
87	110	87	90
88	90	63	75
89	130	92	81
90	100	81	81
91	100	81	81
92	110	93	96
93	98	77	81
94	91	68	73
95	100	80	84
96	93	67	75
97	91	72	77
98	150	110	99
99	150	120	110
100	110	88	97
101	90	73	74
102	99	81	82
103	96	78	81
104	110	93	97
105	93	72	75
106	88	69	73
107	73	54	58

138

108	81	61	65
109	88	33	36
110	130	96	120
111	87	69	75
112	110	78	94
113	94	80	84
114	120	99	100
115	89	71	43
116	—	—	--
117	102	82	85
118	110	84	92
119	110	89	97
120	110	94	97
121	110	90	93
122	100	86	82
123	100	76	73
124	100	8.6	44
125	110	76	78
126	96	74	78
127	130	100	110
128	93	77	78
129	95	79	79
130	130	100	110
131	130	97	110
132	130	110	110
133	120	99	100
134	110	94	100
135	110	97	100
136	120	100	110
137	110	98	110

139

138	—	--	—
139	130	110	120
140	140	120	120
141	130	110	110
142	120	87	93
143	160	150	160
144	110	89	93
145	110	92	94
146	100	88	79
147	1.2	3.1	75
148	110	100	94
149	110	78	81
150	100	67	78
151	110	98	85
152	97	74	74
153	87	67	65
154	85	36	57
155	60	66	73
156	--	—	—
157	94	70	62
158	64	43	41
159	86	55	51
160	<0.1	0.93	73
161	110	91	97
162	100	83	82
163	110	75	73
164	100	72	93
165	120	58	39
166	110	51	64
167	2.1	5.9	83

140

168	110	90	88
169	120	100	97
170	120	96	95
171	120	99	98
172	110	87	85
173	130	98	97
174	99	71	91
175	110	80	85
176	100	77	43
177	110	58	86
178	100	72	86
179	43	92	93
180	100	79	76
181	110	87	88
182	110	81	81
183	110	82	87
184	89	76	76
185	100	83	82
186	110	83	99
187	100	82	83
188	89	77	73
189	89	73	75
190	100	83	87
191	100	85	80
192	—	—	—
193	100	80	73
194	0.68	2.5	78
195	110	83	80
196	89	77	85
197	110	83	79

141

198	120	100	93
199	120	96	92
200	73	73	73
201	87	68	66
202	92	73	70
203	81	70	72
204	82	72	73
205	99	73	81
206	90	71	76
207	82	68	73
208	82	47	57
209	110	81	84
210	110	87	87
211	95	82	78
212	92	79	75
213	85	66	72
214	81	64	69
215	86	70	76
216	—	—	—
217	97	73	69
218	120	85	75
219	110	76	74
220	100	77	86
221	100	72	94
222	85	71	73
223	81	68	69
224	110	78	13
225	95	78	81
226	98	83	86
227	90	73	77

142

228	96	78	81
229	100	81	73
230	100	84	72
231	120	92	87
232	93	74	63
233	98	73	86
234	120	97	91
235	100	83	88
236	110	96	83
237	94	55	52
238	77	55	52
239	91	71	72
240	92	69	67
241	100	81	84
242	110	79	78
243	100	82	81
244	120	99	98
245	100	79	92
246	--	—	—
247	90	75	71
248	94	75	74
249	94	67	93
250	110	81	86
251	100	72	77
252	94	73	62
253	100	75	81
254	100	64	80
255	--	--	--
256	--	--	—
257	--	--	--

143

258

--

—

ASSESSMENT OF METABOLIC STABIL1TY

Objective

The 5 time point, high-throughput human iiver microsome (HLM) metabolic stability assay is designed to détermine in vitro compound metaboiism. Compounds are incubated with HLMs at a concentration of I uM, at 37°C, for a total of 60 min. The percent of compound remaining at 5, 15,30, and 60 min is used to calcul ate the 11/2 (min), CLjnt (mL/min/kg), CLh (mL/min/kg), and % Qh. The assay is based on a 96-well format and can accommodate up to 92 compounds per plate (n=l).

Incubation

Using the 96-well multi-channel head, the Biomek FX, equipped with a Peltier heating block/shaker, is programmed to accompiish the following steps:

1. Pipette 175 uL of 1.15 mg/mL microsomes into each of the 96 conical inserts (Analytical Sales and Products, catalog number 96PL05) that fit into the plate of the Peltier heating block/shaker (the incubation plate)

2. Add 5 uL ofcompounds from the assay plate to the microsomes and shake the mixture at

600 rpm at 42.1°C for 10 min (a setting of42.1°C on the Peltier is required for the sampies to incubate at 37°C)

3. After 10 min, prompt the user to add the NADPH plate to the deck and add 20 uL from the NADPH plate to the incubation plate to start the reaction

4. Add 215 uL of 100%, cold acetonitrile containing an internai standard(s) to a 0 minute, 5 minute, 15 minute, 30 minute, and 60 minute “quench” plate

5. At 0 min, 5 min, 15 min, 30 min, and 60 min into the incubation, aspirate 12 uL from the incubation mixture and add it to the quench solution to stop the reaction

6. Add 185 uL HPLC grade water to each well ofthe 0,5, 15,30 and 60 minute quench plates to dilute compounds to the appropriate concentration for the mass spectrometer

144

Aller ail time points are collected, the quench plates are sealed with 96-well pierceable plate mats or heat sealing foil and centrifuged at 3000 rpm for 15 min to pellet the mîcrosomes.

Analysis

The plates are analyzed using LC/MS/MS with électron spray ionization (ES1) and the previously determined MRM transitions. The LC method includes the following parameters:

Injection volume: 5 uL

Mobile Phases: 0.1% Formic Acid in Water (A) and 0.1% Formic Acid in Acetonitrile (B) 10 (HPLC grade)

Lefl and Right Température: 35 °C

Run Time: 4.0 min

Column: Thermo Scientific, Aquasil C18,50 x 2.1 mm, 5 μ, part number 77505-052130, or équivalent

LC Pump Gradient:

Total Time (min)	Flow Rate (uL/min)	%A	%B
0	500	90.0	10.0
0.5	500	90.0	10.0
1.5	500	1.0	99.0
2.5	500	1.0	99.0
3.3	500	90.0	10.0
4.0	500	90.0	10.0

If peak shape is poor and cannot be integrated properly, the following LC method can be used:

Injection volume: 5 uL

Mobile Phases: 2.5 mM Ammonium Bicarbonate (A) and 100% Acetonitrile (B) (HPLC grade)

Aqueous Wash: 90% Water, 10% Acetonitrile (HPLC grade)

Organic Wash: 90% Acetonitrile, 10% Water (HPLC grade)

Left and Right Température: 35°C

145

Run Time: 4.5 min

Column: Phenomex Luna 3u Cl8(2) 100A, 50 x 2.00 mm

LC Pump Gradient:

Total Time (min)	Flow Rate (uL/min)	%A	%B
0	500	90.0	10.0
0.5	500	90.0	10.0
1.5	500	1.0	99.0
2.5	500	1.0	99.0
3.30	500	90.0	10.0
4.50	500	90.0	10.0

Using an Excel template in Activitybase, the peak areas corresponding to 5, 15,30 and 60 min are compared to the peak area at 0 min to calculate the percent of remaining compound using the following équation:

Percent compound remaining « (AUC at Time t min/AUC at Time 0 min) x 100 where t = 0, 5, 15,30 or 60 min.

Time (min) is plotted against the naturel logarithm (Ln) of the percent compound remaining to détermine the slope. The slope is used to calculate tl/2 (min) using the équation, 11/2 = 0.693/slope.

Clint, Intrinsic clearance • 0.693/tl/2*Avg liver wt in g/avg body wt in kg * f(u)/protein concentration in incubation in mg/mL* mg microsomal protein/g liver • 0.693ΛΙ/2 * 26 g/kg * 1/1.0 mg/mL * 45 mg/g

Clh, Hepatic clearance • Hepatic flow * Ru) * Clint/(hepatîc flow + Ru) * Clint)

146

Qh, % Hepatic blood flow • (Clh/Hepatic flow) · 100

Metabolic stability data (%Qh) for compounds from Table 1 is shown in Table 4 below.

Preferred compounds hâve %Qh values of less than 24.

Table 4

Compound Number.	HLM (%Qh)	Compound Number.	HLM (%Qh)
1	<24	130	25
2	<24	131	28
3	<24	132	<24
4	<24	133	<24
5	<24	134	32
6	<24	135	29
7	<24	136	<24
8	<24	137	<24
9	<24	138	68
10	30	139	<24
11	47	140	<24
12	<24	141	<24
13	<24	142	<24
14	31	143	<24
15	<24	144	<24
16	<24	145	<24
17	31	146	<24
18	<24	147	<24
19	29	148	<24
20	38	149	<24

147

21	<24	150	<24
22	33	151	<24
23	<24	152	<24
24	<24	153	<24
25	29	154	<24
26	29	155	<24
27	<24	156	<24
28	<24	157	31
29	28	158	<24
30	<24	159	<24
31	<24	160	44
32	<24	161	<24
33	<24	162	26
34	<24	163	<24
35	<24	164	<24
36	<24	165	<24
37	<24	166	27
38	<24	167	<24
39	<24	168	<24
40	<24	169	<24
41	<24	170	<24
42	<24	171	<24
43	26	172	<24
44	<24	173	<24
45	<24	174	<24
46	<24	175	31
47	<24	176	28
48	<24	177	<24
49	48	178	<24
50	40	179	<24

148

51	<24	180	<24
52	<24	181	<24
53	<24	182	<24
54	<24	183	<24
55	<24	184	<24
56	<24	185	<24
57	<24	186	<24
58	<24	187	<24
59	<24	188	<24
60	<24	189	26
61	<24	190	43
62	<24	191	<24
63	<24	192	<24
64	<24	193	<24
65	<24	194	<24
66	<24	195	<24
67	<24	196	<24
68	<24	197	<24
69	<24	198	<24
70	<24	199	<24
71	<24	200	40
72	47	201	<24
73	36	202	<24
74	<24	203	<24
75	31	204	<24
76	<24	205	<24
77	<24	206	<24
78	<24	207	<24
79	<24	208	<24
80	<24	209	<24

149

81	<24	210	<24
82	<24	211	<24
83	<24	212	<24
84	<24	213	<24
85	<24	214	<24
86	<24	215	<24
87	<24	216	<24
88	<24	217	89
89	76	218	89
90	<24	219	89
91	<24	220	<24
92	<24	221	<24
93	<24	222	<24
94	<24	223	<24
95	<24	224	<24
96	30	225	<24
97	<24	226	52
98	31	227	25
99	<24	228	44
100	31	229	34
101	<24	230	<24
102	<24	231	<24
103	25	232	<24
104	26	233	26
105	<24	234	<24
106	<24	235	29
107	<24	236	<24
108	<24	237	<24
109	<24	238	<24
110	<24	239	25

150

111	<24	240	<24
112	<24	241	<24
113	<24	242	<24
114	<24	243	<24
115	25	244	<24
116	<24	245	<24
117	25	246	<24
118	<24	247	<24
119	<24	248	<24
120	<24	249	<24
121	<24	250	<24
122	<24	251	<24
123	<24	252	<24
124	<24	253	<24
125	<24	254	<24
126	<24	255	<24
127	<24	256	<24
128	<24	257	<24
129	<24	258	<24

METHODS OF THERAPEUTIC USE

The compounds disclosed herein efiectiveiy activate soluble guanylate cyclase. The activation or potentiation of soluble guanylate cyclase is an attractive means for preventing and treating a variety of diseases or conditions associated with déficient sGC activation. Thus, in one embodiment of the invention, there are provided methods of treating diseases that can be alleviated by sGC activation or potentiation. These include:

Cardiovascular and related diseases including hypertension, atherosclerosis, peripheral artery disease, restenosis, stroke, heart failure, coronary vasospasm, cérébral vasospasm,

151 ischemia/reperfiision injury, thromboembolie pulmonary hypertension, pulmonary arterial hypertension, stable and unstable angina and thromboembolie disorders;

Inflammatory diseases including psoriasis, multiple sclerosis, arthritis, asthma, and chronic obstructive pulmonary disease;

Hepatic fibrotic disorders including but not limited to cirrhosis of any etiology or fibrosis of spécifie areas of the liver such as periportal fibrosis which may be caused by immunologie injury, hémodynamie effects and/or other causes;

Rénal fibrotic disorders including but not limited to glomerulosclerosis, focal glomerulosclerosis, mesangial fibrosis, interstitial fibrosis due to immunologie injury, hémodynamie effects, diabètes (types I and 2),, diabetic nephropathy, IgA nephropathy, lupus nephropathy, membranous nephropathy, hypertension, hemolytic urémie syndrome, multiple glomerulonephritides, interstitial nephritis, tubulointerstitial nephritis again of immunologie and non-immunologie causes;

Pulmonary fibrotic disorders, both diffuse and localized, due to immunologie and nonimmunologie causes, including but not limited to idiopathic pulmonary fibrosis, pulmonary fibrosis due to exposure to toxins, chemicals, dnigs, and cystic fibrosis;

Cardiac fibrotic disorders due to immunologie and non-immunologic causes including ischémie heart disease (coronary artery disease) and transient and/or sustained decreased blood flow in one or more coronary vessels including possibly related to interventions on coronary arteries or 25 veins, associated with cardiac surgery and/or the use of cardiopulmonary bypass procedures and myocarditis due to viral and non-viral causes, as well as immunologically related myocardial injury potentially due to cross-reactivity to other antigens to which the human body is exposed;

Other diseases mediated at least partially by diminished or decreased soluble guanylate cyclase 30 activity, such as rénal disease, diabètes, urologie disorders including overactive bladder, benign

152 prostatic hyperplasia, and erectile dysfunction, and neurological disorders including Alzheimer’s disease, Parkinson’s disease and neuropathie pain.

These disorders hâve been well characterized in man, but also exist with a similar etiology in other mammals, and can be treated by pharmaceutical compositions of the présent invention.

For therapeutic use, the compounds of the invention may be administered via a pharmaceutical composition in any conventional pharmaceutical dosage form in any conventional manner. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable to the particular dosage form selected. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, oral 1 y, topically or by inhalation. The preferred modes of administration are oral and intravenous.

The compounds of this invention may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase 15 inhibitory activity, provide adjunct therapy, and the like, including other active ingrédients. In one embodiment, for example, multiple compounds of the présent invention can be administered. Advantageously, such combination thérapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicily and adverse side effects incurred when those agents are used as monotherapies. Compounds of the invention may be physically combined with the 20 conventional therapeutics or other adjuvants into a single pharmaceutical composition.

Advantageously, the compounds may lhen be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of 25 the invention may vary and is withîn lhe purview of those skilled in the art. Alternatively, the compounds of the présent invention and the conventional therapeutics or other adjuvants may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regimen.

As mentioned above, dosage forms of the compounds of this invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable to the dosage form. These carriers and adjuvants include, for example, ion exchangers,

153 alumina, aluminum stéarate, lecithin, sérum proteîns, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, émulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmacetitical Dosage Forms and Drttg Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements for the compounds of the présent invention may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1 -1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. Astheskilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, spécifie dosage and treatment regîmens will dépend on factors such as the patient's general health profile, the severity and course of the patient’s disorder or disposition thereto, and the judgment of the treating physicïan.

Claims

What is claimed is:

l. A compound of the formula I wherein:

io

A is a 5-7 membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, wherein one carbon of said heterocyclyl group is optionally substîtuted with one or two groups selected from Ct.jalkyl and oxo ;

15 R¹ is Cm alkyl optionally substîtuted with a methoxy group;

R² is selected from H, F, Cl, Cualkyl.-CN, -OMe and -CFj;

R³ is selected from H and -CHj;

R⁴ is selected from H, F, -CHj and -OMe;

155

R⁵ is selected from H, Cl, -CH3, -CH2CH3, -CF3, F, and -OMe;

R⁶ is bonded to the nitrogen on A and is selected from H, Ci^alkyl, -(CH₂)_nC3-6cycloalkyl, C(O)Ci4aIkyl_t -(CH₂)„ heterocyclyl, -(CH₂)_n aryl -(CH₂)„ heteroaryl, -SO₂aryl, SOjC^alkyl

5 wherein said Ci^alkyl, -(CH₂)_n heterocyclyl, -(CH₂)_n cycloalkyl, -(CH₂)_n aryl and -(CH₂)_nheteroaryl are optionally substituted with one to four groups independently selected from C|. 3alkyl, halogen, Ci.saikoxy, -CF3, -OH, oxo, -(CH₂)|.3O(CH₂)₂.3OH, and -SO₂CH3,

R⁷ is selected from H, -CH₃, -CH₂CH₃, -CF3, F, and -CN;

n is 0, 1 or 2 or a sait thereof.
2. The compound according to claim 1, wherein:

A is a 5-7 membered saturated heterocyclyl group containing one nitrogen, wherein one carbon of said heterocyclyl group is optionally substituted with one or two Ci^alkyl groups;

R¹ is Ci.₃alkyl;

R¹ is selected from H, F, Cl, C1.3alkyl.-CN, -OMe and -CF₃;

25 R^J is selected from H and -CH3;

R⁴ is selected from H and F;

R^s is selected from H, Cl and -CH₃;

156

R⁶ is bonded to the nitrogen on A and is selected from H, Ci^alkyl, -(CHi^Cj^cycloalkyl, C(O)C|^a!kyl, -(CH₂)_n heterocyclyl, -(CH₂)_n aryl and -(CH₂)_n heteroaryl, wherein said C|. 6alkyl, -(CH₂)_n heterocyclyl, -(CH₂)_n cycloalkyl, -(CH₂)_n aryl and -(CH₂)_n heteroaryl are optionally substituted with one to four groupe independently selected from Ci.jalkyl, halogen, Cj.jalkoxy, -CFj, -OH and -SO₂CHj_;

R⁷ is H;

and n is 0, 1 or 2;

or a sait thereof.
3. The compound according to daim 1 or 2, wherein:

R¹ is methyl, ethyl or isopropyl; and the group

R⁷ is selected from:

157 and ;

or a sait thereof.
5 4. The compound according to any of daims 1 to 3, wherein:

R² is selected from -CHj, F, Cl, and -CFj; and

R⁶ is selected from H, Ci^alkyl, -(CH₂)_nC3^cycloalkyl, -C(O)Ci^alkyl and -(CHî),, heterocyclyl, 10 wherein said Ci^alkyl, -(CH2)_n cycloalkyl and -(ΟΗ₂)_η heterocyclyl are optionally substituted with one to four groups independently selected from Ci.salkyl, halogen, Cualkoxy, -CF3, -OH and -SO2CH3;

or a sali thereof.

5. The compound according to any of daims 1 to 4, wherein each heterocyclyl referred to in R⁶ is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [l,4]dioxanyl, 8-oxabicyclo[3.2.1]octanyl, l-oxaspiro[4.5]decanyl and pyrrolidin-2-one;

20 each heteroaryl referred to in R⁶ is selected from imidazolyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl and 4,5,6,7-tetrahydrobenzothiazolyl;

and each aryl referred to in R⁶ is phenyl;

158 or a sait lhereof.
6. The compound according to any of daims 1 to 5, wherein:

5 R⁶ is -(CHi)n heterocyclyl, wherein said heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [l,4]dioxanyl, 8oxabicyclo[3.2.1]octanyl and l-oxaspiro[4.5]decanyl;

or a sait thereof.
7. The compound according to any of daims I to 6, wherein:

R²îs-CHj;

R³ is H;

R⁴isHor-CHj;

20 R⁵ is H, or -CHj;

R⁷ is in lhe position para to R⁵ and is H, -CHj or-CH₂CHj;

or a sait thereof.
8. The compound according to any of daims 1 to 7, wherein:

the group

159 or a sait thereof.
9. The compound according to any of daims 1 to 8, wherein:

10 R³ is H; and

R⁴ îs H;

or a sait thereof.

10. The compound according to claim 1 selected from the group consisting of

Cpd No. Structure Cpd No. Structure

160

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1 δ _/OJ Q~ U/ Av- QA7 _K rC K V/ c> > > o ο o CM m en CM CM δ o^ Ç~^~ δ c< Ç-^^- f y .-JL / ^—/ r\_ G· 1’^' Z \ \ A^Z_W U/AJ r\ ΊΚ v) c> > o A o CM m CM CM

i °^ δ A Q- cr\X Z\ °\ ΟΌ _h Q Q > > /A o o v_/ o m m CM CM 5 A 0~ fA °~\ Ο’Χ,ίΧ p=\ °~\ C_z'^z ~v_? —Λλ W'v.? —e~\ (1 q c? m «> m en CM CM

Ο

δ ο- G~ δ ο' θ'' ? ο- -x ο—\ -xdL / »—/ °”\. -xdL / °””\. _-<Κ / -y—/ Q U/A? Q—* S? /V <_> b Q 0 ν> Q Ό οο ο ΓΊ ΥΊ ¥Ί ΓΊ ΓΊ ΓΊ ΓΊ δ Q- δ _ο- Q” δ Q” ·Χ.<Γ>Λ *4θ ~>Λ νΏ 2Κ % b Q b % ¥Ί r~ ο> «Ί η ΓΊ ΓΊ (Ν

253 A Λ 255 AÛ 257 A b?

254 •’cAÇ¹^ 256 _o ,> 258 Ar N_x Z^-o •

and the pharmaceutically acceptable salts thereof.

5

11. The compound according to claim 10 selected from the group consisting of compound numbers 1, 2, 3,4, 5, 7, 8, 9, 12, 15, 16,18, 21, 27, 28, 30, 31, 35, 36, 39, 41,42,44,45,46, 47, 48, 57,59, 62, 68, 77, 78, 79, 80, 82, 83, 84, 85, 86, 88, 92, 93, and 94 and the pharmaceutically acceptable salts thereof.

193
12. The compound according to daim 10 seleted from the group consisting of compound numbers95, 97, 100, ΙΟΙ, 102, 103,104, 105, 106,107,108, 109, HO, lll, ll2, ll3, H4, ll5, H6, ll7, ll8, ll9,120, I2l, 122,123,124, 125,126, 127,128,129, 130, I3l, 132,136, 137, 139,140, I4l, 142, 145, 146,152, 153, 154, 155, 157, 158, 159,161,162,163, 164, 165,166, 167,169, 170,17l, 172, 173, 174, 175,176, 177,178, 179, 180,I8l, 184, 185,186,187, 188, 189, I9l, 193, 194,195, 196, 197,198, 199, 201,202, 203, 204,205, 206, 207,208, 210, 211, 212,213,214,215,216,220,222,223,224,225,227,229,230,231,232,233,234,235,236, 237,238,239,240,241,242,243,244,246,247,248,249,250,251,252,253,254,255,256, 257 and the pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a compound according to any of daims ] to 12 and a pharmaceutically acceptable excipient or carrier.
14. Use of a compound according to any of daims ] to 12 in the manufacture of a médicament for treating a disease or disorder that can be alleviated by sGC activation or potentiation.
15. The use according to daim 14 wherein the disease or disorder is selected from a cardiovascular disease, înflammatory disease, hepatic fibrotic disorder, rénal fibrotic disorder, pulmonary fibrotic disorder and cardiac fibrotic disorder.
16. The use according to daim 14 wherein the disease is selected from rénal disease, overactive bladder, benign prostatic hyperplasia, erectile dysfonction, Alzheîmer’s disease, Parkinson’s disease and neuropathie pain. ‘
17. The use according to daim 14 wherein the disease is diabetic nephropathy.