CZ20001340A3 - Isoquinolines functioning as urokinase inhibitors - Google Patents

Abstract

Compounds of formula I, pharmaceutically acceptable salts wherein one of R 1 and R 2 is H and the remaining is N = C (NH 2) 2 or NHC (= NH) NH 2 and other substituents have specificity of importance are urokinase inhibitors (uPA)

Description

Isoquinolines as urokinase inhibitors

Technical field

The present invention relates to certain isoquinolines useful as urokinase inhibitors, in particular isoquinolinylguanidines useful as urokinase inhibitors.

BACKGROUND OF THE INVENTION

Urokinase (urinary-type plasminogen activator or uPA; International Union of Biochemistry classification number EC.3.4.21.31) is a serine protease produced by a large number of different cell types (smooth muscle cells, fibroblasts, endothelial cells, macrophages and tumor cells). They have been shown to play an important role in cell invasion and tissue transformation. The base substrate for uPA is plasminogen, which is converted by cell surface bound uPA to yield serine protease plasmin. Locally produced high concentrations of plasmin mediate cell invasion by an extracellular matrix disorder. Important procedures involving cell invasion and tissue transformation include wound healing, bone remodeling, angiogenesis, tumor invasiveness, and metastasis development.

Satisfactory effects of urokinase inhibitors have been described using antiurokinase monoclonal antibodies and certain other known urokinase inhibitors. For example, anti-urokinase monoclonal antibodies have been described as blocking cellular invasiveness in vitro (W. Hollas, et al., Cancer Res. 51: 3690; A. Meissauer, et al., Exp. Cell. Res. 192: 453 (1991); metastasis and in vivo invasion (L. Ossowski, J. Cell Biol. 107: 2437 (1988)); L. Ossowski, et al., Cancer Res. 51: 274 (1991)) and angiogenesis in vivo (JA Jerdan et al. J. Cell Biol 115 [3 Pt 2]: 402a (1991).

Also, Amilorid ™, a known inhibitor of mild potency of urokinase, is reported to be an inhibitor of tumor metastasis in vivo (J.A.

Kellen et al., Anticancer Res., 8: 1373 (1988) and angiogenesis and capillary network formation in vitro (M.A. Alliergo et al., J.

Cell Biol. 115 [3 Pt 2]: 402 (a).

Conditions of particular interest for treatment with urokinase inhibitors include chronic skin ulcers (including venous ulcers and sores and pressure sores), which are an important cause of morbidity in the aging population and pose significant economic problems in the health system. Chronic skin ulcers are characterized by an excess of uncontrolled degradation leading to ulcer spread, loss of functionality of matrix molecules (e.g. fibronectin) and retardation of epithelization and ulcer healing. A number of research groups have investigated enzymes that cause excess degradation in the wound environment and the role of plasminogen activators has been elucidated (MC Stacey et al., Br. J. Surgery, 80, 596; M. Palolahti et al., Exp. Dermatol. , 1993; AA Rogers et al., Wound Repair and Regen., 3, 273 (1995). Normal human skin exhibits low levels of plasminogen activators that are localized to blood vessels and identified as plasminogen activator (tPA). In contrast, chronic ulcers exhibit high levels of urokinase-type plasminogen activator (uPA), localized dispersed at the edge and in the ulcer lesion and are readily detectable in wound fluid.

uPA can act on wound healing in several ways. Plasmin, produced by plasminogen activation, can cause extracellular matrix collapse by both indirect (via activation of matrix metalloprotease) and direct methods. Plasmin has been shown to degrade some components of extracellular matrix components, including gelatin, fibronectin, proteoglycan core proteins, as well as its main substrate, fibrin.

While activation of matrix metalloproteases (MMPs) can be accomplished by a variety of inflammatory cellular proteases (e.g., elastase and cathepsin G), the uPA / plasmin cascade can be demonstrated in MMP activation in situ, providing a broad capacity for degradation of all extracellular matrix components. Furthermore, in addition to this effect on plasmin production, uPA has been shown to catalyze the direct cleavage of fibronectin to form antiproliferative peptides. Thus, overexpression of uPA in the wound environment strongly promotes uncontrolled matrix degradation and inhibition of tissue recovery. Enzyme inhibitors are effective in promoting chronic wound healing.

Some related enzymes, such as tPA, which also act through plasmin production, play an important role in the fibrinolytic cascade. Consequently, it is important that the inhibitor have adequate potency and selectivity to both uPA and tPA and plasmin in order to avoid antifibrinolytic side effects.

The usefulness of such potent and selective urokinase inhibitors is illustrated by the wide range of urokinase-mediated invasive biological procedures. Procedures include, but are not limited to, wound healing, angiogenesis-dependent conditions, conditions such as retinopathy, bone remodeling, implantation of an embryo into the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue transformation during wound healing and organ differentiation, fibrosis, local tumor invasion into adjacent areas, metastatic development of tumor cells from primary sites to secondary sites, and tissue destruction in arthritis.

Various aromatic amidines have been reported which inhibit uPA (J.D. Geratz, M.C.F. Cheng, Thromb. Diathes. Haemorrh. (Stuttg.),

33, 230 (1975); Sturzebecher, J. Markwardt, Pharmazie, 33, 599 (1978); J.D. Geratz et al., Thromb. Res. 24, 73 (1981). The compounds disclosed in these publications are relatively weak and / or nonselective to uPA than to other related serine proteases. EP 0 568 289 A2 discloses a series of benzo [b] thiophene-2-carboxamidines with substantially greater potency and selectivity with respect to tPA and plasmin (see also M.J. Towle and < tb > < tb >

et al., Cancer Res. (53, 2553, 1993; A. J. Bridges et al., Bioorg. Med. Chem., 1, 403, 1993).

There are several reports of guanidine derivatives as uPA inhibitors. Amiloride ™ (see below) is a weak but selective inhibitor of uPA (JD Vassalli, D. Belin, FEBS Letters, 214, 187, 1987), and variously substituted phenylguanidine phenylguanidines are reported to have the same potency (H. Yang et al., J Med. Chem., 33, 2956 (1990).

Amiloride

SUMMARY OF THE INVENTION

The compounds of the invention are potent reversibly-competitive inhibitors of urokinase enzymatic activity, with urokinase selectivity relative to certain other important proteases, including the tissue-type plasminogen activator phybrinolytic enzymes (tPA) and plasmin.

The selectivity of the claimed compounds for inhibiting urokinase exceeds that of other proteases such as tPA and plasmin, and the fact that they inhibit reversibly protects them from thrombogenic properties.

The present invention provides isoquinolinylguanidine derivatives of formula I:

or a pharmaceutically acceptable salt thereof, wherein one of R ¹ and R ² is hydrogen and the other is N = C (NH ₂ ) ₂ or NHC (= NH) NH ₂ ,

R ³ is H, halogen, C 1-6 alkyl, optionally substituted with one or more halogen atoms or C 1-6 alkoxy, optionally substituted with one or more halogen atoms,

R ⁴ , R ⁵ , R ⁸ and R ⁷ are each independently H, OH, halogen, C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen or OH, C 1-6 alkoxy, optionally substituted one or more halogens, CN, CO (C 1-8 alkyl, optionally substituted with one or more halogens), (C 1-4 -alkylene) CO 2 R ⁸ , (C 1-4 -alkylene) CN,

0 (C _n -alkylene) CN, 0 (C _n -alkylene) CO ₂ R ⁸ , (C m-alkylene) CONR ⁹ R ¹⁰ (C m-alkylene) NR ⁹ COR ¹⁰ , 0 (C _n -alkylene) CONR ⁹ R ^10, (C _m - alkylene) NR ⁹ SO 2 R ^{1 L,} (Cm - alkylene) S (O) p R ^11, (C _m - alkylene) SO ₂ NR ⁹ R ^10, CH = CHCOR ^8, CH = CHCONR ⁹ R ¹⁰ ,

CH = CHSO ₂ R ⁸ , CH = CHSO ² NR ⁹ R ¹⁰ , CH = CHSO 2 aryl, or a group of formula X-aryl or X-het, or wherein two of R ⁴ , R ⁵ , R ⁶ and R ⁷ are bonded to adjacent atoms carbon and may together form part of -O (C _n -alkylene) O-,

R ⁸ is H, C _1-4 alkyl, optionally substituted with one or more halogen or aryl (C 1-8 alkylene),

R ⁹ and R ¹⁰ are each independently H, C- ^ g alkyl, optionally substituted by one or more halogen, aryl (C ₁ _G alkylene)

9

99 aryl, heteroaryl or heteroaryl (C ₁ _G alyklen) or and R 10 may bond together to form alkylene moiety, with the atoms to which they are attached, a 4- to 7-membered ring optionally containing another hetero atom selected from 0 or S or NR ¹² ,

R ¹¹ is aryl, heteroaryl or C _L _G alkyl optionally substituted with one or more halogens,

R ¹² is H, C 1-8 alkyl, optionally substituted with one or more halogens or CO (C 1-8 alkyl, optionally substituted with one or more halogens),

X is a direct bond, C _n - alkylene, 0 (C _n - alkylene) 0 0 (C _n -alkylene), CH (OH), C (C ₁ _ ₆ alkyl) 0H, CO, S (O) _p ( C _m - alkylene), (C _m - alkylene) S (0) p, CH = CH or C≡C, aryl is phenyl or naphthyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen or OH, C ₁ _G alkoxy optionally substituted by one or more halogen, CN, 0 (C _n - alkylene) CN, (C _n

- alkylene) CN, CO (C ₁ _G alkyl, optionally substituted with one or more halogens), (C _m - alkylene) CO ₂ R ^13, 0 (C _n

- alkylene) CO ₂ R ^13, (C _m - alkylene) CONR ¹⁴ R ^15, (C _m - alkylene) NR ¹⁴ C0R ¹⁵ 0 (C _n - alkylene) CONR ¹⁴ R ^15,

R ¹³ , (C 1-4 alkylene) SO ² NR ¹⁴ R ¹⁵ , (C ¹⁶ , ch = chso2r ¹³ , ch = chso2nr ¹⁴ r ¹⁵ ,

CH = CHSO ₂ aryl ^1, CH = CHCOR ^13, and CH = CHCONR ¹⁴ R ^15, (C _m - alkylene) S (0). - alkylene) NR ¹⁴ SO ₂ R heteroaryl is an optionally benzocondensed 5- or 6-membered heterocyclic group bonded by any suitable atom in the heterocycle or benzene ring (if present), wherein the heterocyclic group is selected from dioxolyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, 9 9 9 9 9 9 9 9 9 9 9 9

9999

9

9 ·

9 9

9 ·

9

99

9 9 · · ·

9 9 9 '9 · 9 9

99 pyridazinyl, pyrazinyl and pyranyl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₁ _G alkyl optionally substituted with one or more halogens or OH, C ^ g alkoxy, optionally substituted with one or more halogens, CN, O ( _Cn

- alkylene) CN, (C _n - alkylene) CN, CO (C ₁ _G alkyl, optionally substituted with one or more halogens), (C _m

- alkylene) CO ₂ R ^13, 0 (C n - alkylene) CO 2 R ^13, (cm

CONR ¹⁴ R ¹⁵ , (C 1-4 alkylene) NR ¹⁴ COR ^15.0 (Cn

- alkylene) CONR ¹⁴ R ^15, (cm alkylene) NR ¹⁴ SO 2 R ^16, (C _m

- alkylene) S (O) pR ¹³ , (C 1-4 alkylene) SO ² NR ¹⁴ R ¹⁵ , CH = CHCOR ¹³ , CH = CHCONR ¹⁴ R ¹⁵ , CH = CHSO ² R ¹³ , CH = CHSO ² NR ¹⁴ R ¹⁵ , CH = CHSO ² aryl, het is optionally a benzofused 5- or 6-membered heterocyclic group bonded to the X moiety by any suitable atom in the heterocycle or benzene ring (if present), wherein the heterocyclic group is selected from dioxolyl, dioxolanyl, furyl, thienyl, pyrrolyl, oxazolyl, oxazinyl, thiazinyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl or their fully saturated, partially or fully saturated analogs wherein said het is or more substituents independently selected from the group consisting of halogen, C j__g alkyl optionally substituted with one or more halogen and OH, C ₁ _G alkoxy optionally substituted by one or more halogen, CN, 0 (C _n

- alkylene) CN, (C _n - alkylene) CN, CO (C | __g alkyl, optionally substituted with one or more halogens), (C _m

alkylene) CO ₂ R ¹³ , O (C ¹¹ - alkylene) CO ₂ R ¹³ , (Cm -

- alkylene) CO ¹⁴ R ¹⁵ , (C 1-4 alkylene) NR ¹⁴ CO ¹⁵ , O (C 11

- alkylene) CO ¹⁴ R ¹⁵ , (C 1-4 alkylene) NR ¹⁴ SO ² R ¹⁶ , (C _m

- alkylene) S (0) p R ^13, (C m - alkylene) S02NR ¹⁴ R ^15, CH = CHCOR ^13, CH = CHCONR ¹⁴ R ^15, CH = CHSO2R ¹³ CH CHSO2NR ¹⁴ R ¹⁵ and CH = CHSO2aryl ¹

V • · · 0 · ·

0 ···· · · · ·

0 · 0 · 0

0 · 0 0

0 0 ¹ · aryl is phenyl or naphthyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, C ₁ _G alkyl, optionally substituted with one or more substituents independently selected from halogen or OH,

C ₁ _G alkoxy optionally substituted by one or more halogen, CN, 0 (C _n - alkylene) CN, (C _n - alkylene) CN, CO (C ₁ _G alkyl, optionally substituted with one or more halogens), (C _m - CO ₂ R 13,0 (C ¹¹ -alkylene) CO ₂ R ¹³ , (C 1-4 -alkylene) CONR ¹⁴ R ¹⁵ (C, alkylene) NR ¹⁴ COR 'n »15

0 (C τη alkylene) CONR ¹⁴ R ^15, (C _m - alkylene) S (O) p R ^13, (C m - alkylene) SO 2 NR ¹⁴ R ^15, (C m - alkylene) NR ¹⁴ S0 ₂ R

CH = CHCOR ¹³ and CH = CHCONR ¹⁴ R ¹⁵ , ch = chso ₂ r ¹³ , ch = chso ₂ nr ¹⁴ r ¹⁵ ,

R ¹³ is H, C 1-6 alkyl, optionally substituted with one or more halogens, or aryl ² (C 1-8 alkylene),

^R14 and ^R1 ^ are each independently selected from the group consisting of hydrogen, C- ^ g alkyl, optionally substituted with halogen, aryl ² (C ₁ _G alkylene), aryl ^2, heteroaryl ¹ or heteroaryl ¹ (C-j__g alkylene) or R ¹ and R ¹ may be bonded together with an alkylene moiety to form, with the atoms to which they are attached, a 4- to 7-membered ring, optionally containing an additional hetero group selected from O or S, or NR ¹² ,

R ¹⁶ is aryl ^2, heteroaryl ¹ or C ₁ _G alkyl, optionally substituted with one or more halogen, aryl ² is phenyl or naphthyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, C j__g alkyl optionally substituted with one or more substituents independently selected from halogen or OH, Cj__g alkoxy optionally substituted by one or more halogen, CN, 0 (C _n - alkylene) CN, (C _n - alkylene) CN, or CO (Cj__g alkyl, optionally substituted one or more halogens), * · · · · * * * * * * * * * * * * * * * * * * * Heteroaryl ¹ is an optionally benzocondensed 5- or 6-membered heterocyclic group bonded by any suitable v atom. a heterocycle or benzene ring (if present) wherein the heterocyclic group is selected from dioxolyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, tetrazolyl, tetrazolyl, tetrazolyl, tetrazolyl, tetrazolyl , pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl, wherein said heteroaryl is a group which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, optionally substituted with one or more substituents independently selected from halogen or OH, C 1-4 alkyl; ₆ alkoxy optionally substituted by one or more halogen, CN, 0 (C _n - alkylene) CN, (C _n - alkylene) CN, or COfC- ^ g alkyl, optionally substituted with one or more halogens), wherein the C-alkylene groups mentioned binding in the definitions above are linear or branched and are optionally substituted by one or more (0 _1-6 alkyl groups, optionally substituted I one or more halogen) groups, m is an integer from 0 to 3, n is an integer from 1 to 3;

p is an integer from 0 to 2.

Pharmaceutically acceptable salts are well known to those skilled in the art, and examples include those disclosed by Berge et al. in J. Pharm.

Sci., 66, 1-19 (1977). Suitable acid addition salts are formed from acids that form non-toxic salts and include hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, acetates, and the like. · · · · · · · ···

99 ·

9 9 9 9 ·

9 9 9 9 • -fc «« ·

- 10 trifluoroacetates, gluconates, lactates, salicylates, citrates, tartrates, ascorbates, succinates, maleates, fumarates, gluconates, formates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates and p-toluenesulfonates.

When one or more substituents on a compound of Formula I contain an acidic moiety, suitable pharmaceutically acceptable base addition salts may be formed from bases which form nontoxic salts and include aluminum, calcium, lithium, magnesium, potassium, sodium, zinc salts and pharmaceutically acceptable salts. active amines such as diethylamine salts.

Alkyl groups include the alkyl portion of the alkoxy groups and can be straight or branched chain or cyclic where the number of atoms allows.

Halo includes fluorine, chlorine, bromine and iodine.

Certain compounds of formula I may exist as geometric isomers. Certain compounds of Formula I may exist as tautomers. The compounds of formula I may have one or more asymmetric centers and thus exist in two or more stereoisomeric forms. The present invention includes all individual tautomers, stereoisomers and geometric isomers of the compounds of Formula I and mixtures thereof.

Preferably R ¹ is N = C (NH ₂ ) ₂ or NHC (= NH) NH ₂ and R ² is H. Preferably, at least two of R ⁴ , R ⁵ , R ⁶ and R ^{7 are} H.

Preferably R ³ is H, halogen or C _1-4 alkyl, optionally substituted with one or more halogen atoms. More preferably, R ^{3 is} H, Cl, Br or methyl, optionally substituted with one or more halogen atoms. Most preferably RH, Cl or methyl.

9 * 999 * * «• 9 9 ·% 9999 ·

9 9 ·

• · »

9 • 9 • 9

- 11 Preferably, R ⁴ is H, OH, halo, C- ^ g alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen or OH, C ₁ _G alkoxy optionally substituted by one or more halogen, CN, _(Cm -alkylene) CONR @ ⁹ R @ ^10, 0 (Cn -alkylene) CONR ⁹ R ^{18, 1} (Cm-alkylene) SO ₂ NR ⁹ R ¹⁸ or a group of formula X-aryl or X-het.

More preferably, R ⁴ is H, Br, OH, CN, C ₁ _G alkoxy, alkyl, optionally substituted by one or more OH, SO ₂ NR ⁹ R ^18, CONR ⁹ R ^10, R ¹⁰ OCH2CONR ^9, OCH2aryl, Het or aryl.

Even more preferably, R ⁴ is H, Br, OH, CN, C 1-8 alkoxy, C 1-8 alkyl, optionally substituted with one or more groups selected from the group consisting of OH, SO ² NR ⁹ R ¹⁸ , CONH (aryl (C 1-6 alkyl)) , CONH 2, OCH ₂ CONR ⁹ R ¹⁰ , OCH ₂ aryl, phenyl or naphthyl.

Most preferably R ⁴ is H, Br, CN, OCH ₃ , SO ₂ NH ₂ , CH ₂ OH, CONH ₂ , OCH ₂ CONH ₂ , CONHBn, OBn, OH or Ph.

Preferably, R ⁵ is H, halo or C] __ g alkyl optionally substituted by one or more substituents independently -vybranými from halogen or OH.

More preferably, R ⁵ is H, Br or methyl, optionally substituted with one or more halogen atoms.

Most preferably R ⁵ is H, Br or methyl.

Preferably, R ⁶ is H, halogen, C ₁ _G alkyl optionally substituted with one or more substituents selected from the group consisting of halogen or OH, C | __g alkoxy optionally substituted by one or more halogen, CN, 0 (C _n - alkylene) CN, (C _n - alkylene) CN, (C _m - alkylene) CONR ⁹ R ^10, (C m - alkylene) CO 2 R ^8, (C m - alkylene) SO ₂ NR ⁹ R ^8, (C _m - alkylene) S (O) p R ⁴¹ or a group of formula X-aryl or X-het.

More preferably, R ⁶ is H, Cl, Br, O-C 1-6 alkyl, optionally substituted with one or more substituents selected from the group consisting of OH, alkoxy, CN, (C 1-4 alkylene) CO ⁵ R ⁹ R ¹⁰ , (C 1-4)

- alkylene) CO ₂ R ⁸ , (C 1-4 alkylene) S (O) p R ^{1: L} (C 1-4 alkylene) SO ₂ NR ⁹ R ¹⁰ • or a group of formula X-aryl or X-het, where X is a direct bond , CH = CH, CH (OH), CO, OCH ₂ , CH ₂ O or CH ₂ .

Even more preferably, R ⁶ is H, Br, methyl optionally substituted by OH, ethyl optionally substituted by OH, cyclopentyl optionally substituted by OH, cyclohexyl optionally substituted by OH, C-j__g alkoxy, CN, O (C _n - alkylene) CN, ( ( _N -alkylene) CN, SO ₂ R ¹¹ ,

SR ¹¹ , CONR ⁹ R ¹⁰ , CO ² R ⁸ , SO ² NR ⁹ R ¹⁰ , a group of formula X- (optionally substituted phenyl) or X-het ¹ , wherein X is a direct bond, CH = CH, CH (OH), CO, OCH ₂ , CH ₂ O or CH ₂ , and wherein the phenyl moiety bonded via X is optionally substituted with one or more halogen, C _1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen and OH, C _1-6 alkoxy, optionally substituted with gednim or more of halogen or CO ₂ R, wherein het ¹ is optionally benzofused dioxolyl, furyl, thienyl, imidazolyl, or partially or fully saturated analogs thereof, and wherein such het ¹ group bonded via X is optionally substituted with one or more C 1-6 alkyls; g is optionally substituted with one or more substituents independently selected from halogen and OH.

Further, more preferably R ^{8 is} H, Br, CO ₂ H, (E) CH = CHPh, Ph, OCH ₃ ,

1,3-benzo [d] dioxol-5-yl, CN, _CH2 OH, CONHBn, 4-methoxyphenyl,

1-hydroxycyclohexyl, 1-hydroxycyclopentyl, COPh, CH (OH) CH ₃ , CH (OH) Ph, CCH ₃ (OH) Ph, OCH ₂ Ph, SO ₂ Ph, SPh, CH ₂ OPh, SO ₂ NH ₂ , SO ₂ NHPh, SO ₂ NH (cyclopentyl), SO ₂ (pyrrolidino),

S0 ₂ (morpholino), S0 ₂ (N-methylpiperazino), (2-methylimidazol-1-yl) methyl, (2-methylbenzo-imidazol-1-yl) methyl, benzofuran-2-yl, thien-3-yl, thien -2-yl, 4-methylpentyl,

2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl,

2,6-dimethoxyphenyl, 3-carboxyphenyl, 3-cyanophenyl or

3-chlorophenyl.

Most preferably, R ⁶ is CH (OH) Ph, 2-methoxyphenyl, 3-methoxyphenyl,

4-methoxyphenyl, 2,6-dimethoxyphenyl, SO ₂ NH ₂ , SO ₂ NHPh,

SO ₂ NH (cyclopentyl), SO ₂ (pyrrolidino), SO ₂ (morpholino), SO ₂ Ph, SPh, SO ₂ (N-methylpiperazino) or 3-carboxyphenyl.

· 4 4 4 4

4 ·

Preferably R ⁷ is Η.

A preferred group of compounds is that wherein R ¹ is N = C (NH 2) 2 or NH (C (= NH) NH 2, each of R ² , R ⁴ , R ⁵ and R ⁷ are H, R ³ is Br or Cl and r 6 is 2-methoxyphenyl, 4-methoxyphenyl, CH (OH) Ph, SO 2 Ph,

SPh, 3-carboxyphenyl or 3-methoxyphenyl.

Another preferred group of compounds are those wherein two of R ⁴ , R ⁵ , R ⁶ and R ⁷ are bonded to adjacent carbon atoms and together form part of OCH ₂ O.

Yet another preferred group of compounds are those of the Examples and salts thereof.

Most preferred compounds are selected from the group consisting of:

(4-chloro-7- (2-methoxyphenyl) isoquinolin-1-yl) guanidine;

(4-chloro-7- (3-methoxyphenyl) isoquinolin-1-yl) guanidine;

(4-chloro-7- (4-methoxyphenyl) isoquinolin-1-yl) guanidine;

(4-chloro-7- (2,6-dimethoxyphenyl) isoquinolin-1-yl) guanidine; (4-bromo-7- (3-methoxyphenyl) isoquinolin-1-yl) guanidine;

(4-bromo-7- (4-methoxyphenyl) isoquinolin-1-yl) guanidine;

(4-chloro-7- (α-hydroxybenzyl) isoquinolin-1-yl) guanidine; (4-chloro-7- (3-carboxyphenyl) isoquinolin-1-yl) guanidine;

1-guanidino-7-sulfamoylisoquinoline;

1-guanidino-7-phenylsulfamoylisoquinoline;

4-chloro-1-guanidino-7-phenylsulfamoylisoquinoline;

4-chloro-7-cyclopentylsulfamoyl-1-guanidinoisoquinoline;

4-chloro-1-guanidino-7- (1-pyrrolidinosulfonyl) isoquinoline hydrochloride;

4-chloro-1-guanidino-7-morpholinesulfonylisoquinoline hydrochloride 4-chloro-1-guanidino-7 - [(N-methylpiperazino) sulfonyl] isoquinoline;

4-chloro-1-guanidino-7- (phenylsulfanyl) isoquinoline;

4-chloro-1-guanidino-7- (phenylsulfonyl) isoquinoline;

- 14 and their salts.

Another aspect of the present invention is a pharmaceutical composition comprising a compound or salt as defined above and a pharmaceutically acceptable adjuvant, carrier or diluent.

Yet another aspect of the present invention is a compound or salt as defined above for use as a medicament.

Another aspect of the present invention is the use of a compound or salt as defined above for the preparation of a medicament for treating a condition or process mediated by uPA, such as chronic cutaneous ulcer, angiogenesis (neovascularization), bone remodeling, implantation of the embryo into the uterus; ovulation, spermatogenesis, tissue transformation during wound healing and organ differentiation, fibrosis, local tumor invasion into adjacent areas, metastatic development of tumor cells from primary sites to secondary sites, and tissue destruction in arthritis.

Another aspect of the present invention is a method of treating a condition or process mediated by uPA, such as chronic cutaneous ulcer, angiogenesis (neovascularization), bone remodeling, implantation of embryo into the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue transformation during wound healing and organ differentiation, fibrosis, local tumor invasion into adjacent areas, metastatic deployment of tumor cells from primary sites to secondary sites, and tissue destruction in arthritis, comprising administering a therapeutic amount of a compound or salt or composition as defined above.

It will be appreciated that reference to treatment includes prophylaxis and alleviation of the symptoms of uPA-mediated conditions.

♦ 8 • · · ·

The invention further provides methods for preparing the compounds of the invention, which are described below and in the Examples. One of skill in the art will appreciate that the compounds of the invention may be prepared by methods other than those described in the description of the invention, by applying the methods described herein below and / or by adapting them and by methods known in the art.

In the methods set forth below, unless otherwise indicated, substituents have the meaning given in the references to a compound of Formula 1.

Method 1

Compounds of formula I may be obtained from the corresponding compounds

1- or 3-aminoisoquinoline derivative of the general formula II:

by reaction with cyanamide (NHCN) or a reagent that acts as NHC ⁺ = NH synton, such as carboxamidine derivatives, for example 1H-pyrazole-1-carboxamidine (MS Bernatowicz, Y. Wu, GR Matsudea, J. Org. Chem., 1992 57, 2497), its 3,5-dimethylpyrazole analogue (MA Brimble et al., J. Chem. Soc. Perkin Trans. I (1990), 311), simple O-alkylthiouronium salts or S-alkylisothiouronium salts such as O-methylisothiourea (F. El-Fehail et al., J. Med. Chem. (1986), 29, 984), S-methylthiouronium sulfate (S. Botros et al., J. Med. Chem. (1986) 29874; PS Chauhan et al.,

Indian. J. Chem., 1993, 32B, 858) or S-ethylisothiouronium bromide (M. L. Pedersen et al. J. Org. Chem. (1993) 58, 6966). Alternatively, aminoiminomethanesulfinine • H may be used

- 16 acid or aminoiminomethanesulfonic acid (A. E.

Miller et al., Synthesis (1986) 777; K. Kim et al., Tet.

Lett. (1988) 29,383).

Other methods for this transformation are known to those skilled in the art (see, for example, Comprehensive Organic Group Transformatios, 1995, Pergamon Press, Vol. 6, p. 639, TL Gilchrist (Ed.); Patai: Chemistry of Functional Groups, Vol. 2 The Chemistry of Amidines and Imidates, 1991, 488).

Aminoisoquinolines II can be prepared by standard published methods (see, for example, The Chemistry of Heterocyclic Compounds, Volume 38, Part 2, John Wiley & Sons, Ed. FG Kathawala, GM Coppolq, HF Schuster), including, for example, rearrangement from the corresponding carboxy derivative Hoffmann, Curtius, Lossen, Schmidt) and subsequent deprotection.

Alternatively, amino aminoquinolines II can be prepared by direct replacement of a leaving group such as Cl or Br with a nitrogen nucleophile such as azide (followed by reduction) or ammonia, or by catalysis of Pd via a suitable amine (e.g. benzylamine) followed by deprotection using standard conditions known in the art. state of the art.

1- (Chloro or bromo) isoquinolines can be prepared by treating the corresponding N-oxides of formula III with POCl 3 or βηβ in an inert solvent such as methylene chloride at reflux.

(III) ·· ····

• · · · · · · · · · · · · · · · ·

Haloisoquinolines are commercially available or can be prepared by various methods, for example, those described by Goldschmidt, Chem. Ber. (1895) 28, 1532; Brown and Plasz, J. Het. Chem. (1971 6, 303; U.S. Patent 3,930,837; Hali et al., Can. J. Chem. (1966) 44, 2473; White, J. Org. Chem. (1967). 32, 2689; and Ban, Chem. Pharm Bull (1964) 12, 1296.

1,4- (Dichloro- or dibromo) isoquinolines can be prepared by the methods described by M. Robinson et al. in J. Org. Chem. (1958) 23, 1071, by reacting the corresponding compound with isokarbostyrylové PC1 ₅ or PBr _fifth

Method 2

Compounds of formula I may be prepared from the corresponding aminoisoquinoline derivative as defined in method I above by reaction with a reagent that acts as a protected amidine (2+) synthon IV,

2+

PNH

NHP, (IV) such as PNHC (= X) NHP ₁ , PN = CXNHP ₁ or PNHCX = NP ₁ , wherein X is a leaving group such as Cl, Br, I, mesylate, tosylate, alkyloxy etc., wherein P and P1 may be the same or different and are N-protecting groups such as those well known in the art, such as tert-butoxycarbonyl, benzyloxycarbonyl, arylsulfonyl such as toluenesulfonyl, nitro, etc.

Examples of reagents that act as synthons of IV include N, N'-protected-S-alkylthiouronium derivatives such as N, N'-bis (tert-butoxycarbonyl) -S-Me-isothiourea,

N, N ¹ bis (benzyloxycarbonyl) -S-methylisothiourea or their sulfone derivatives (J. Org. Chem., 1986, 51, 1882) or S-arylthiouronium derivatives, such as · · · · · · · · · · · · · · · · · · · · · ·

- 18 Ν, Ν'-bis (tert-butoxycarbonyl) -S- (2,4-dinitrobenzene) (S. Lammin, BL Bedgrift, AJ Ratcliffe, Tet. Lett. 1996, 37, 6815) or mono-protected analogs such as is [(4-methoxy-2,3,6-trimethylphenyl) sulfonyl] carbamimidothionic acid methyl ester or the corresponding 2,2,5,7,8-pentamethylchroman-6-sulfonyl analogs (DR Kent, WL Cody, AM Doherty, Tet) Lett., 1996, 37, 8711) or S-methyl-N-nitrosoisothiourea (L. Fishbein et al., J. Am. Chem. Soc. (1954) 76, 1877) or differently substituted thioureas such as Ν, Ν'-bis (tert-butoxycarbonyl) thiourea (C. Levallet, J. Lerpiniere, SY Ko, Tet. 1997, 53, 5291) with or without the presence of a promoter such as Mukaiyama's reagent (Yong, Y.

F., Kovalski, J.A .; Lipton, M.A.J. Org. Chem., 1997, 62, 1540) or salts of copper, mercury or silver, in particular mercuric chloride. Suitable N-protected O-alkylisoureas may also be used such as O-methyl-N-nitrosoisothiourea (N. Heybor et al. Rec. Chim. Trav. Pays-Bas (1962) 81, 69). Alternatively, guanylating agents known to those skilled in the art, such as 1H-pyrazole-1- [N, N'-bis (tert-butoxycarbonyl) carboxamidine, the corresponding bis-Cbz derivative (MS Bernatowicz, Y Wu, GR Matsudea, Tet. 1993, 34, 3389) or monoBoc or mono-Cbz derivatives (B.

Drake, Synthesis, 1994, 579, by M. S. Bernatowicz. Tet. Lett. 1993, 34, 3389). Similarly, 3,5-dimethyl-1-nitroguanylpyrazole can be used (T. Wakayima et al., Tet. Lett. (1986) 29, 2143).

The reaction is conveniently carried out using a suitable solvent such as dichloromethane, N, N-dimethylformamide (DMF), methanol.

The reaction is also conveniently carried out by adding copper (II) chloride to a mixture of aminoisoquinoline (II) and a thiourea type IV derivative in a suitable base / solvent mixture such as triethylamine / dichloromethane.

φ »····

9

9 9 9 9 9

9,999 99 99

9 9 9 9 9 9 9 9

9 9 9

9 9 9

The product of this reaction is protected isoquinolinguanidine V, which can be conventionally treated to remove the protecting group to give I or a salt thereof. For example, when P and / or P 1 is t-butoxycarbonyl, the deprotection is conveniently carried out using an acid such as trifluoroacetic acid (TFA) or hydrochloric acid in a suitable solvent such as dichloromethane to give the bistrifluoroacetate salt I.

When P and / or P 1 is a hydrogenolysable group such as a benzyloxycarbonyl group, deprotection is performed by hydrogenolysis.

Other protecting / deprotection regimens include: nitro (K. Suzuki et al., Chem. Pharm. Bull. (1985) 33, 1528, Nencioni et al., J. Med. Chem. (1991) 34, 3373, BT Golding et al., JCS Chem Comm (1994) 2613;

p-toluenesulfonyl (J.F. Callaghan et al. Tetrahedron (1993))

3479;

mesitylsulfonyl (Shiori et al., Chem. Pharm. Bull. (1987) 35, 2698, ibid. (1987) 35, 2561, ibid. (1989) 37, 3432, ibid. (1987) 35, 3880, ibid. (1987) 35, 1076;

2-adamantoyloxycarbonyl (Iuchi et al., Ibid. (1987) 35, 4307; and methylsulfonylethoxycarbonyl (Filippov et al., Syn. Lett. (1994) 922)

It will be apparent to those skilled in the art that in the preparation of the compounds according to the invention

9999 • · · · ···· · · 9 9 ·

9

9 9 · 9 9

9

99 99

Other methods for protecting a functional group and subsequently removing a protecting group can be used, for example, as described in Protective Groups in Organic Synthesis, T W Green and P G M Wuts, John Wiley and Sons Inc. (1991) and as described by P.J. Kocienski in Protective Groups, Georg Thieme Verlag (1994).

Method 3

Compounds of formula I wherein R ¹ is guanidinyl and R ² is H or R ¹ is H and R ² is guanidinyl may be obtained from compounds of formula VI:

wherein Z is attached at the 1- or 3-position as appropriate and a leaving group such as Cl, Br or OPh is suitable by replacing the leaving group with a free base of guanidine.

The guanidine free base may conveniently be generated in situ from a suitable salt such as a hydrochloride, carbonate, nitrate or sulfate with a suitable base such as sodium hydride, potassium hydride or other alkali metal bases, preferably in a dry non-protic solvent such as tetrahydrofuran (THF) ), DMSO,

N, N-dimethylformamide (DMF), ethylene glycol dimethyl ether (DME), Ν, Ν-dimethylacetamide (DMA), toluene or mixtures thereof. Alternatively, it may be generated from a suitable salt using an alkoxide in a suitable alcoholic solvent such as potassium tert-butoxide in tert-butanol or a non-protic solvent as described above.

0 * 0 0

0 0 0

00000

0 0

0 0

00 0000

0 0 0 0 ·

0 0 0

0 0

0

00

0 0 *

0 0 0

0 0 0 0

0 0 0

00

The thus formed guanidine may be combined with 1- or

The 3-isoquinoline derivative and the reaction to give compounds of formula (I) may be carried out at room temperature to 200 ° C, preferably from about 50 ° C to 150 ° C, preferably for between 4 hours and 6 days.

Method 4

ZL 7

Compounds of formula I wherein one or more R is or contains a hydroxy group may be prepared from a suitably protected hydroxy derivative, i.e., compounds of formula I wherein one or more of R ^4-7 is or comprises OP ² , where P ^{2 is an} appropriate O a protecting group such as O-benzyl. For example, the benzyl group may be removed by catalytic hydrogenation using palladium on charcoal as a catalyst in a suitable solvent such as ethanol at about 20 ° C and elevated pressure, optionally in the presence of an excess of acid such as HCl or AcOH or TFA or other known methods for removal. protecting groups.

Suitable protecting groups and protecting / removing protecting groups can be found in the texts of Green and Wuts and Koncienski above.

Method 5

Compounds of the invention wherein R ⁴ -R ⁷ is or contains a carboxyl group or a carbamoyl group may be prepared from the corresponding compound wherein the substituent is a nitrile by total or partial hydrolysis. Compounds of the invention wherein R ⁴ -R ⁷ is or contains a carboxylic acid group can be prepared from the corresponding compound wherein the substituent is a carbamoyl moiety by hydrolysis. Hydrolysis can be carried out by methods well known in the art, for example as described in Advanced Organic Chemistry J.

· 4

ΦΦΦ Φ Φ

4 Φ Φ ΦΦΦΦ 4 4 4

ΦΦΦ Φ Φ

ΦΦ Φ ΦΦ

Φ Φ φ φ φ φ φ φ • • • • φ φ φ φ

Φ Φ Φ Φ φφφφ

March, 3rd Edition (Wiley-Interscience), Chapter 6-5 and references cited therein. Conventionally, the hydrolysis can be carried out using concentrated hydrochloric acid at elevated temperature and the product forms the hydrochloride salt.

Method 6

Where desired or necessary, the compound of formula (I) is converted to its pharmaceutically acceptable salt. A pharmaceutically acceptable salt of a compound of Formula I may conveniently be prepared by mixing solutions of a compound of Formula I and the desired acid or base as appropriate. The salt may precipitate out of solution and be collected by filtration or may be collected by other means, such as evaporation of the solvent.

General methods of interconversion

Compounds of formula I wherein one or more R 1 -R ⁷ is or contains Cl or Br may be dehalogenated to give the corresponding hydride compounds of formula I by hydrogenolysis, suitably using palladium on activated carbon as a catalyst, in a suitable solvent such as ethanol at about 20 ° C and at elevated temperature.

Compounds of formula I wherein R ¹ is guanidinyl and one or more R ⁴ -R ⁷ is or contains a carboxy group may be prepared from a compound having a hydrolyzable group to give a carboxyl moiety, for example the corresponding nitrile or ester, by hydrolysis, for example acid hydrolysis with e.g. conc. aqueous HCl at reflux. Other methods of hydrolysis are known in the art.

Δ. 7

Compounds of formula I wherein one or more R-Rs contain an amide moiety may be prepared by reaction of an optionally protected corresponding carboxyl compound, either by direct coupling with an amine or via the initial formation of the corresponding amine moiety.

9

9

9 9 9 9 9 9 9 9 9 9 9

9,999 99 9

9

9 99

The acid chloride is then reacted with an amine and then deprotected if appropriate. Such transformations are well known in the art.

Some of the compounds of formula I having an electrophilic group attached to the aromatic ring may be prepared by reacting the corresponding hydride compound with an electrophilic agent.

For example, the sulfonylation of the aromatic ring using standard methods such as fuming sulfuric acid provides the corresponding sulfonic acid. This can then optionally be converted to the corresponding sulfonamide by methods known in the art, for example by first converting it to a sulfonyl chloride followed by reaction with an amine.

Some of the compounds of the invention may be prepared by cross-coupling techniques, such as reacting a compound containing a bromine substituent attached, for example, to an aromatic ring, with, for example, a boronic acid derivative, olefin or tin derivative by methods known in the art. .

Some of the compounds of the invention having an electrophilic substituent may be prepared through halogen / metal exchange and subsequent reaction with an electrophilic reagent. For example, a bromo substituent may be reacted with a lithium reagent such as n-butyllithium followed by an electrophilic reagent such as CO ₂ , an aldehyde or a ketone to form the corresponding acid or alcohol.

The compounds of the invention are available either by the methods described herein in the methods and examples or by their suitable adaptation using methods known in the art. It should also be taken into account that synthetic transformation methods here • 4 44 «4 4 4« 444 «4 4 4 4 • 4 4 4 4

44 · 4

4 4 * 4 • · 4 · 44 · 4 · · 4 · 44 · 4 ·

4 4 4 4

4 44

The foregoing can be accomplished by a variety of sequences that result in the effective preparation of the desired compound. One of skill in the art can use his experience to select the most efficient sequence of reactions to prepare the desired compound.

One skilled in the art will recognize that during the synthesis of the compounds of the invention, protecting groups may need to be introduced and removed to protect sensitive groups. This deprotection and deprotection can be accomplished using conventional procedures such as those described in Protective Groups in Organic Synthesis, TW Grene and PGM Wuts, John Wiley and Sons Inc (1991) and PJ Kocienski in Protective Groups, Georg Thieme Verlag (1994).

The compounds and their salts of the invention may be separated and purified by conventional means

Separation of diastereomers may be accomplished by conventional means, for example, fractional crystallization, chromatography, or H.P.L.C of a stereisomeric mixture of a compound of Formula I or a suitable salt thereof. The individual enantiomer of a compound of Formula I may also be prepared from the corresponding optically pure intermediate or by resolution into enantiomers such as the H.P.L.C of the corresponding racemate using a suitable chiral carrier or by fractional crystallization of diastereomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base.

The compounds of formula (I) or salts thereof may be administered to humans alone, but are usually administered in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier selected with respect to the route of administration chosen and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets, including sublingually, in the form of tablets containing such excipients as starch, lactose, or in the form of capsules or ovules containing the compound of the invention. * · 4 44 44 4444 • 9 4 44 4 Λ4 44

Either alone or mixed with excipients. The compounds may also be administered in the form of elixirs, solutions or suspensions containing aromatics or coloring agents. The compounds of the invention may also be administered parenterally, for example by intravenous, intramuscular or subcutaneous injection. For parenteral administration, sterile aqueous solutions which may contain other substances, for example, salts or glucose in an amount sufficient to render the solution isotonic with blood, will be most suitable. They can be administered topically in the form of sterile creams, gels, suspensions, lotions, ointments, powders, sprays, medicines introduced by dressings or skin. For example, they may be incorporated into a cream containing an aqueous or oily emulsion of polyethylene glycol or liquid paraffin or may be incorporated into an ointment containing a white waxy paraffin base or hydrogel with cellulose derivatives or popyacrylate derivatives or other viscosity modifiers or dry powder or liquid spray or aerosol using propellants. butane / propane, HFA or CFC or drugs incorporated into dressings, for example tulle dressings with white soft paraffin or polyethylene glycol impregnated gauze dressings or with hydrogel, hydrocolloid, alginate or film dressings. The compound or salt can also be administered intraocularly as eye drops with suitable buffers, viscosity modifiers (eg, cellulose derivatives), preservatives (eg, benzalkonium chloride (BZK)) and tackifiers, such as sodium chloride.

All formulations may also contain suitable stabilizers and preservatives.

For oral or parenteral administration to humans, a daily dose in the range of from 0.001 to 20, preferably from 0.01 to 20, more preferably from 0.1 to 10, and most preferably from 0.5 to 5 mg is suitable for the compounds of formula I or salts thereof. / kg (in single or multiple doses). The tablets or capsules of the compounds will contain from 0.1 to 500, preferably from 50,

26 to 200 mg of the active compound and, as appropriate, will be administered once, twice or more times a day.

In any case, the physician will determine the most appropriate dose for each patient, which dose will vary depending on the age, weight and response of the patient to the preparation administered. The above dosages are merely exemplary dosages for the average patient, and, of course, there may be individual cases where higher or lower dosages will have to be administered.

It will be appreciated that references to treatment also include prophylaxis and alleviation of the symptoms of the condition to be treated.

Test methods.

The compounds were tested for their ability to inhibit human urokinase, human tPA and human plasmin, using essentially the same methods described by Yang et al., J. Med.

Chem., (1990) 33, 2961. The urokinase assay was performed using S-2444 (Quadratech 820357) as a substrate and HMWT Human Urokinase (Calbiochem 672081) was used as urokinase. The tPA assay was performed using S-2288 (Quadratech 820832) tPA substrate, Quadratech 321116 as a tPA stimulator, and Human tPA (Quadratech 881157) was used as tPA.

Plasmin assay was performed using human plasmin (Quadratech 810665) acting on Chromozyme-PL (Boehringer).

378461) as a substrate.

As shown below, the substances of the invention are selective inhibitors of UPA:

Example No. Ki_UPA (NM) vs. tPA * vs plasmin *

249 380 204

400 88 68

35 63> 1000 280.

* selectivity value

Some of the compounds of the invention are named as guanidine derivatives and some as isoquinoline derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Melting points were determined using a Gallenkamp apparatus and are uncorrected. Nuclear magnetic resonance data was obtained using a Varian Unity 300 or Varian Lin 400 spectrometer and is reported in parts per million of tetramethylsilane. Mass spectral data was obtained on Finnigan Mat. TSQ 7000 or Fisons Instruments Trio 1000. The calculated and observed ions are reported to be the lowest weight relative to the isotopic composition. The term ether, unless otherwise indicated, means diethyl ether. Ph is phenyl, Bn is benzyl, and Me is methyl. TLC means thin layer chromatography. TFA means trifluoroacetic acid.

Example 1: Isoquinolinylguanidine

Sodium hydride (192 mg, 60% dispersion in mineral oil, 4.8 mmol) was added in one portion under nitrogen atmosphere at room temperature to guanidine hydrochloride (465 mg, 4.9 mmol) in DMSO (6.0 mL) and the mixture is stirred until the evolution of hydrogen ceases. 1-Chloroisoquinoline (300 mg, 1.83 mmol) was then added and the mixture was heated at 100 ° C for 3 days. The solvent was removed in vacuo and the residue was directly purified • · «·» • • · · * ^1> · «• · ··

- 28 column chromatography on silica gel using dichloromethane: methanol: ammonia 0.880 (95: 5: 0.5 to 90: 10: 1) as eluant to give 1-isoquinolinylguanidine (195 mg, 1.0 mmol) as a white solid substance.

M.p. 165 [deg.] C .; - ¹ H NMR (δ, DMSO-d 6, 400 MHz) 6.95 (1 H, d), 7.4 (1H, dd), 7.55 (1 H, dd), 7.65 (1 H, d), 7.85 (1H, d) 8.55 (1H, d); LRMS 187 (MH < + >), 373 (M ₂ H); Elementary analysis -found: C, 61.66; H, 5.37 ; N, 29.10. . Calculated for (Ζ ^ θΗ- ^) ₀ N ₄ + 0.45 H ₂ O; C, 61.81 H, 5.61 5; N,

28.83.

Other compounds prepared by the same general method using the appropriate starting materials are listed in Table 1 below.

Examples 2 and 3 are characterized as the corresponding hydrochloride salts, prepared by adding ethereal HCl to the base solution and evaporating to dryness.

Examples 28 and 29 are characterized as the trifluoroacetate salts prepared by dissolving the free base in trichloroacetic acid and evaporating to dryness.

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Example 52: salt

3-Isoquinoliguanidine and its bis (trifluoroacetate)

(TFA) 2

Mercury (II) chloride (192 mg, 0.707 mmol) was added in one portion under N ₂ and at 23 ° C to a stirred mixture of 3-aminoisoquinoline (84.5 mg, 0.586 mmol), N, Ν'-di-tert-butoxycarbonyl- S-methylisothioureas (Bergeron, R.J .; McManis, JSJ Org. Chem. 1987, 52, 1700-1703) (204 mg, 0.703 mmol), and triethylamine (250 μΐ, 1.79 mmol) in CH ₂ Cl ₂ ( 3.0 ml). The mixture was stirred for 26 hours and then directly purified by silica gel column chromatography using hexanes-EtOAc (98: 2 to 95: 5) as eluant to give 3- (Ν ', N' ^1- di-tert-butoxycarbonyl- N-guanidinyl) isoquinoline (189.4 mg, 0.492 mmol) as a white solid.

¹ H NMR (δ, CDCl ₃ , 300 MHz) 1.55 (18, s), 7.45 (1H, dd), 7.65 (1H, dd), 7.85-7.9 (2H, m) ), 8.7 (1H, br s), 9.0 (1H, s), 10.5 (1H, br s), 11.6 (1H, br s);

LRMS 387 (MH &lt; + &gt;).

Trifluoroacetic acid (2.5 mL) was added to a solution Ι-ίΝ ', Ν ¹ ' -di-tert-butoxycarbonyl-N-guandinyl) isoquinoline (181 mg,

0.468 mmol) in CH ₂ Cl ₂ (1.5 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with CH ₂ Cl ₂ (5 mL) and the solvent was evaporated in vacuo to give bis (trifluoroacetate) 3-isoquinolinylguanidine (186.9 mg, 0.449 mmol) as a white solid.

NMR (δ, MeOH-d ₄ , 400 MHz), 4.8-5.0 (4H, br s), 7.4 (1H, s), 7.6 (1H, dd), 7.75 (1H) dd), 7.85 (1H, d), 8.05 (1H, d), 9.1 (1H, S);

LRMS 187 (MH &lt; + &gt;);

Found: C, 40.46; H, 2.77; N, 13.36.

4

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4 «

4 ·

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Calcd. For C 12 H 11 N 2 O 2 + 2 TFA: C, 40.59; H, 2.92; N, 13.52.

Example 53: (5-Hydroxyisoquinolin-1-yl) guanidine

A solution of (5-benzyloxyisoquinolin-1-yl) guanidine (290 mg, 1.0 mmol) in EtOH (10 mL) containing 10% Pd-C (60 mg) and dilute HCl (1.5 mL, 2 M, 3, 0 mmol) was stirred at 60 ° C for 3 days under H ₂ atmosphere. Additional catalyst (30 mg) and HCl (0.5 mL) were added and hydrogenation continued for a further 3 days. The mixture was filtered through Arbocel, washed with EtOH, and the filtrate evaporated in vacuo and the residue purified by silica gel column chromatography using dichloromethane: methanol: 0.88 ammonia (90: 10: 1 to 84: 14: 2) as eluant and to give (5-hydroxyisoquinolin-1-yl) guanidine (66 mg, 0.33 mmol) as a white solid.

M.p. > 150 DEG C. decomposition;

NMR (δ, DMSO-d6, 400 MHz), 3.0-3.4 (1H, br s), 7.05 (1H,

d), 7.35 (1H, dd), 7.4-8.4 (3H, br s), 7.45 (1H, br s), 7.95 (1H, d), 8.1 (1H) d) 10.5-11.0 (1H, br s);

LRMS 203 (MH &lt; + &gt;);

Found: C, 52.00; H, 5.35; N, 23.00. Calcd for C ₁₂ H ₁₁ N ₄ O + 0.66H ₂ O + 0.3CH ₂ Cl ₂ : C, 51.64; H, 5.01; N, 23.38.

4 »4 9999 4 4

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Example 54: (7- (4-Methoxyphenyl) isoquinolin-1-yl) guanidine

A solution of (4-bromo-7- (4-methoxyphenyl) isoquinolin-1-yl) guanidine (38 mg, 0.1 mmol) and industrial methylated alcohol (2.0 mL) containing 5% Pd-C (10 mg) Stir under H ₂ (0.35 MPa) at 23 ° C for 3 days. The mixture was filtered through Arbocel ™, washed with ethanol, the filtrate evaporated in vacuo and the residue purified by silica gel column chromatography using dichloromethane: methanol: 0.88 ammonia (97: 3: 0.3) as eluant to afford ( (7- (4-methoxyphenyl) isoquinolin-1-yl) guanidine (24 mg, 0.08 mmol) as a white solid.

Mp > 174 ° C;

¹ H NMR (δ, DMSO-d 6, 400 MHz), 3.25 (4H, br s, exchangeable), 3.8 (3H, br s), 7.05 (2H, d), 7.5-7 Δ (1H, m), 7.85 (2H, d), 8.0 (1H, d), 8.05-8.15 (2H, m), 8.75 (1H, s);

LRMS 293 (MH &lt; + &gt;).

Example 55

(7- (3-Carboxyphenyl) -4-chloroisoquinolin-1-yl) guanidine hydrochloride o

HCI »this • this • this • this • this • this

• this • •· it «

A solution of (4-chloro-7- (cyanophenyl) isoquinolin-1-yl) guanidine (69 mg, 0.21 mmol) in concentrated hydrochloric acid (10 mL) was refluxed for 20 hours. After cooling, the precipitate was filtered off, washed with water and dried under high vacuum at 0 ° C to give the title salt (55 mg, 0.16 mmol) as an off-white powder.

Mp 312-316 ° C;

¹ H NMR (δ, DMSO-d ₆ , 300 MHz) 13.4-11.2 (1H, br s), 9.4-7.8 (5H, br s), 9.2 <1H, s) 8.45-8.1 (5H, m), 8.0 (1H, d), 7.65 (1H, t);

LRMS 341, 343 (MH);

Found: C, 53.25; H, 3.80; N, 14.28. Calcd for C ₁₇ H ₁₄ Cl ₂ N ₄ O ₂ + 0.33 H ₂ O: C, 53.29; H, 3.86; N, 14.62.

Example 56 (i) 1-Guanidino-7-sulfamoylisoquinoline

NH,

Guanidine hydrochloride (42 mg, 0.44 mmol) was added in one portion to a suspension of NaH (13 mg, 80% dispersion by weight in mineral oil, 0.43 mmol) in DMSO (1.5 mL) and the mixture was heated to 60 ° C under N ₂ for 30 minutes. 1-Chloro-7-isoquinolinesulfonamide (37 mg, 0.152 mmol) was added and the mixture was heated to 100 ° C for 24 hours. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography using CH ₂ Cl ₂ -MeOH-0.880NH ₃ (97: 3: 0.3 to 90: 10: 1) as eluant to give the title compound ( 34 mg, 0.13 mmol) as an off-white solid.

«· ··· ·

Melting point 198-200 ° C (decomposition).

¹ H (DMSO-d 6, 400 MHz) δ 7.0 (1H, d), 7.1-7.4 (4H, br s), 7.3 (2H, s), 7.8 (1H, d) 7.9 (1H, d), 8.0 (1H, d), 9.1 (1H, s) ppm.

LRMS 266 (MH ^&lt; ^{+ &gt;} ).

Found: C, 41.38; H, 3.97; N, 24.09. Calculated for ^C 10 ^H 11 ^N 5 ^O 2 ^S - ° ^{C 05CH} 2 ^Cl 2 ^{> 1} ' ^1H 2 ^{O: C} ' ⁴¹ ' ⁷² ' ^H ' ⁴ < ⁶³ ' ^{N '24.20} .

(ii) 1-Guanidino-7-sulfamoylisoquinoline dihydrochloride 1-Guanidino-7-sulfamoylisoquinoline (12 mg, 0.045 mmol) was dissolved in a solution of ethanol saturated with HCl gas (1.0 mL) and the mixture was stirred at room temperature for 1 hour. The solvents were evaporated in vacuo and the residue azeotroped with dichloromethane (CH 2 Cl 2) to give 1-guanidino-7-sulfamoylisoquinoline dihydrochloride (13 mg, 0.043 mmol) as a white solid.

¹ H (DMSO-d 6, 400 MHz) δ 7.6 (2H, s), 7.7 (1H, d), 8.2 (1H, s), 8.2 (1H, d), 8.3 (1H, d), 8.4-9.0 (4H, br s), 9.1 (1H, d), 11.0 (1H, s) ppm.

Found: C, 34.80; H, 3.85; N, 19.68. Calcd for ^C 10 ^H 11 ^N 5 ^O 2 ^S - ^2HCl - ^O ' ^5H 2 ^O -1' ^{EtOH: C} ' ³⁴ '⁸²; ^H, 4.18; N, 19.91.

Example 57

1-Guanidino-7-phenylsulfamoyl quinoline

Guanidine hydrochloride (100 mg, 1.05 mmol) is added in one portion to a suspension of sodium hydride (NaH) (30 mg, 80% dispersion, by weight in mineral oil, 1.0 mmol) in dimethylsulfoxide (DMSO) (3, 5 ml) and the mixture is heated to 60 ° C under nitrogen (N ₂ ) 4 4. · ·· 4 ·· »

- 44 for 30 minutes. 1-Chloro-7-phenylsulfamoylisoquinoline (110 mg, 0.345 mmol) was added and the mixture was heated at 100 ° C for 3 days. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, using CH ₂ Cl ₂ -methanol-0.880NH ₃ (97: 3: 0.3 to 90: 10: 1) as eluant) to give 1-guanidino -7-phenylsulfamoylisoquinoline (16 mg,

0.047 mmol) as an off-white solid.

Melting point 186-188 ° C.

¹ H (DMSO-d 6, 400 MHz) δ 6.95 (2H, d), 7.05 (2H, d), 7.1-7.3 (4H, br s), 7.15-7.2 (2H, m), 7.7 (1H, d), 7.75 (1H, d), 8.0 (1H, d), 9.0 (1H, s), 10.2 (1H, s) ppm.

LRMS 341 (MH ^&lt; ^{+ &gt;} ).

Found: C, 51.44; H, 4.14; 19.50. Calculated for ^C 10 ^H 15 ^N 5 ^O 2 ^S - o ^'1CH 2 ^C1 2 ^{1' 2} H2 ^{O: C; 52 to 05; H,} 4.78; N, 18.85.

Example 58 (i) 4-Chloro-1-guanidino-7-sulfamoylisoquinoline

Guanidine hydrochloride (70 mg, 0.73 mmol) was added in one portion to a suspension of NaH (21 mg, 80% dispersion in mineral oil, 0.66 mmol) in DMSO (2.0 mL) and the mixture was heated to 50 ° C under N ₂ for 30 minutes. 1,4-Dichloro-7-sulfamoylisoquinoline (70 mg, 0.25 mmol) was added and the mixture was heated to 90 ° C for 18 hours. The cold mixture was partitioned between ethyl acetate (EtOAc) and water and the organic phase was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was separated by silica gel column chromatography using CH ₂ Cl ₂ -MeOH-0.880NH ₂ (95: 5: 0.5 to 90: 10: 1) as eluant to give 4-chloro-1-ol. -guanidino-7-sulfamoylisoquinoline (50 mg, 0.167 mmol) as a white solid.

Mp 230 ° C (dec.).

¹ H (DMSO-d 6, 300 MHz) δ 7.1-7.5 (4H, br s), 7.4 (2H, br s), 8.0 (1H, d), 8.1 (1H, S), 8.15 (1H, d), 9.1 (1H, s) ppm.

LRMS 300, 302 (MH ^&lt; ^{+ &gt;} ), 599 (M &lt; _{2 &gt;} H ^&lt; ^{+ &gt;} ).

Found: C, 39.49; H, 3.37; N, 22.63. Calcd for ^C 10 ^H 10 ^ClN 5 ° 2 ^S - ° ^25H 2 ^{O: C} '39.48; ^H , 3.48; N, 23.02.

(ii) 4-Chloro-1-guanidino-7-sulfamoylisoquinoline hydrochloride

4-Chloro-1-guanidino-7-isoquinolinesulfonamide (30 mg, 0.10 mmol) was dissolved in EtOH solution saturated with HCl gas (2.0 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue azeotroped with CH ₂ Cl ₂ to give 4-chloro-1-guanidino-7-isoquinolinesulfonamide hydrochloride (32 mg, 0.095 mmol) as a white solid.

Melting point 296 ° C (dec.).

¹ H (DMSO-d 6, 400 MHz) δ 7.6 (2H, s), 7.7 (1H, d), 8.2 (1H, s), 8.2 (1H, d), 8.3 (1H, d), 8.4-9.0 (4H, br s), 9.1 (1H, d), 11.0 (1H, s) ppm.

LRMS 300, 302 (MH ^&lt; ^{+ &gt;} ), 599 (M &lt; _{2 &gt;} H ^&lt; ^{+ &gt;} ).

Found: C, 35.55; H, 3.26; N, 20.13; Calculated for ^C 10 ^H 10 ^C1N 5 ^S 2 ^O - ^{1 '0HC1 <0' 5 CH} 2 ^{C1 2: C} '35.46; H, 3.29; N, 20.57.

Example 59

4-Chloro-7-cyclopentylsulfamoyl-1-guanidinoisoquinoline

The title compound was prepared by the same general method as in Example 56.

Melting point > 250 ° C (decomposition).

· * · O (DMSO-d6, 400 MHz) δ 1.2-1.4 (4H, m), 1.4-1.6 (4H, m), 3.4 (1H, m), 7, 7-7.8 (1H br d), 8.0-8.2 (2H, m), 9.1 (1H, s) ppm. LRMS 368 (MH ^&lt; ^{+ &gt;} ).

Found: C, 48.23; H, 4.97; N, 18.44. Calculated for ^C 15 ^H 18 ^C1N 5 ^S 2 · ° ^{0 '1CH} 2 ^{C1 2: C' 48/19} » ^'4/87; N, 18.61.

Example 60

4-Chloro-1-guanidino-7- (1-pyrrolidinosulfonyl) isoquinoline hydrochloride

The title compound was prepared by the same general method as in Example 56.

Mp 299-300 ° C.

^X H (DMSO-d₆, 300 MHz) δ 1.6-1.7 (4H, m), 8.2 to 8.9 (4H, br s), • φ · · · · · φ φ φ φ · φ · · «· · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ * · · · Φφ φφ

- 47 8.3 (1Η, d), 8.4 (1Η, d), 8.5 (1Η, s), 9.1 (1Η, s) ppm. LRMS 354 ( ⁺ ).

Found: C, 43.71; Η, 4.69; N, 16.67. Calculated for ^C 14 ^H 16 ^C1N 5 ^S 2 ° - ^HC1 - o ^{'3EtOAc: C' 43 '81' 'H' 4 '69'} · ^N '16.81

Example 61

4-Chloro-1-guanidino-7-morpholinosulfonylisoquinoline hydrochloride

The title compound was prepared by the same general method as in Example 56.

Melting point 285 ° C (dec.).

1 H (trifluoroacetic acid-d, 400 MHz) δ 3.4 (4H, s), 4.1 (4H, S), 8.3 (1H, d), 8.5 (1H, s), 8, 65 (1H, d), 9.1 (1H, s) ppm.

LRMS 370, 372 (MH ^&lt; ^{+ &gt;} ).

Found: C, 41.69; H, 4.32; N, 16.17. Calcd for ^C 14 ^H 16 ^ClN 5 ^O 3 ^{S, HCl} - ^{5MeOH; C '41' 24} '· ^{H' 4/53; N} , 16.58.

Example 62

4-Chloro-1-guanidino-7 - [(N-methylpiperazino) sulfonyl] isoquinoline

The title compound was prepared by the same general method as in Example 56.

Melting point 262-263 ° C (decomposition).

¹ H (trifluoroacetic acid-d, 400 MHz) δ 3.1 (3H, s), 3.3 (2H, m), 3.4 (2H, m), 3.9 (2H, m), 4, 2 (2H, s), 8.3 (1 H, d),

8.5 (1H, s), 8.7 (1H, d), 9.0 (1H, s) ppm.

LRMS 383, 385 (MH ^&lt; ^{+ &gt;} ).

Found: C, 46.70; H, 4.99; N, 21.62. Calculated for ^C 15 ^H 19 ^ClN 6 ° 2 ^S - 25 ' ^{25MeOH: C} ' ⁴⁶ ' ⁸⁶ ' · ^H '5.16; N, 21.50.

Example 63

4-Chloro-1-guanidino-7- (phenylsulfanyl) isoquinoline

NaH (13.6 mg, 80% dispersion, wt in mineral oil, 0.45 mmol) was added in one portion to a solution of guanidine hydrochloride (44 mg, 0.46 mmol) in DMSO (2 mL) and the mixture was heated at 80 ° C under N ₂ for 10 minutes. 1,4-Dichloro-7- (phenylsulfanyl) isoquinoline (60 mg, 0.195 mmol) was added and the mixture was stirred for 4 hours.

4 · · · · · · · · ·

- 4ίΓ44 4 · · · · · · · · · · · · · · · · ·

Heat at 80 ° C for 1 hour. The cold mixture was poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was extracted with hexanes-i-Pr ₂ O and this organic solution was decanted and then stirred with a solution of HCl in Et ₂ O to give a precipitate. The white solid was collected by filtration and dried in vacuo to give 4-chloro-1-guanidino-7- (phenylsulfanyl) isoquinoline (51 mg, 0.13 mmol).

¹ H (DMSO-d 6, 300 MHz) δ 7.3-7.5 (5H, m), 7.7 (1H, d), 8.1-9.2 (4H, br s), 8.1 (1H, d), 8.3 (1H, s), 9.0 (1H, s), 11.3 (1H, s) ppm.

LRMS 329 (MH ^&lt; ^{+ &gt;} ).

Found: C, 50.54; H, 3.95; N, 14.81. Calculated for ^C 16 ^H 13 ^C1N 4 ^S - ^HC1 - o ^'75H 2 ^{0: C' 5θ '73'} · ^H '4.12; N, 14.79.

Example 64

4-Chloro-1-guanidino-7- (phenylsulfonyl) isoquinoline

NaH (18 mg, 80% dispersion, by weight in mineral oil, 0.60 mmol) was added in one portion to a solution of guanidine hydrochloride (90 mg, 0.94 mmol) in DMSO (2 mL) and the mixture was heated at 50 ° C. ° C under N ₂ for 30 minutes. 1,4-Dichloro-7- (phenylsulfonyl) isoquinoline (80 mg, 0.236 mmol) was added and the mixture was heated to 50-60 ° C for 0.5 h. The cold mixture was poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was dissolved in EtOAc and the residue was dissolved in EtOAc and dissolved in EtOAc. · · · · ····

- 5δ ·

a solution of HCl in Et ₂ O (1M) was added and a precipitate was obtained.

The solvent was evaporated in vacuo and the residue was triturated with EtOAc to give 4-chloro-1-guanidino-7- (phenylsulfonyl) isoquinoline (65 mg, 0.18 mmol) as a yellow solid.

⁴ H (DMSO-d 6, 400 MHz) δ 7.6-7.75 (3H, m), 8.1-9.2 (4H, br s), 8.2 (2H, d), 8.35 (1H, d), 8.4 (1H, d), 8.45 (1H, s), 9.5 (1H, s), 11.7 (1H, s) ppm.

LRMS 361 (MH ^&lt; ^{+ &gt;} ).

Found: C, 48.17; H, 3.75; N, 3.16. Calculated for ^C 16 ^H 13 ^ClN 4 ° 2 ^S - ^HCl - ⁰ ' ^25H 2 ^O - °' ^{2EtOAc: C} ' ⁴⁸ ' ^{1: L} '· ^H ' ^{3 '87} ; ^N, 13.36.

Preparation 1

4.7- Dibromoisoquinoline

Bromine (2.77 mL, 53.8 mmol) was added dropwise over 20 minutes to a stirred suspension of a 1: 1 mixture of 5- and 7-bromoisoquinoline hydrochloride (prepared by cyclization of dimethyl (3-bromobenzylidene) aminoacetal according to the procedure described in FT). Tyson J. Am Chem Soc., 1939, 61, 183-5) (11.43 g, 48.2 mmol) in nitrobenzene (12.5 mL) and the mixture was heated at 170 ° C for 5 hours. The mixture was cooled to 80 ° C, diluted with toluene (50 mL) to give a precipitate which was left at 23 ° C overnight. The mother liquors were decanted with toluene (2 x 20 ml). The solid was precipitated with aqueous sodium hydroxide (100 mL, 1 M), extracted with ether (3x100 mL), and the ether phase was dried over magnesium sulfate (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (96: 4 to 80:20) as eluant to give

4.7- dibromoisoquinoline (5.91 g, 20.6 mmol) as a white solid.

Melting point 107-110 ° C.

¹ H (δ, CDCl ₃ , 300 MHz) 7.9 (1H, d), 8.05 (1H, d), 8.15 (1H, s), 8.75 (1H, S), 9.1 (1 H, s);

LRMS 285,287 (MH).

• to · to · to · to · 51 · to · to · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · to · ·· · this ·

Found: C, 37.90; H, 1.67; N, 4.83. Calcd. For C ₉ H ₅ Br ₂ N: C, 37.67; H, 1.76; N, 4.88.

Preparation 2

4-Bromo-7-phenylisoquinoline

A mixture of 4,7-dibromoisoquinoline (556 mg, 1.93 mmol), tetrakis (triphenylphosphine) palladium (0) (73 mg, 3 mol%), phenylboronic acid (238 mg, 1.95 mmol) and aqueous sodium carbonate (Na ₂ CO ₃ ) (3.9 mL, 1.0 M, 3.9 mmol) in DME (12 mL) was refluxed under nitrogen for 20 hours. The mixture was diluted with ethyl acetate (EtOAc) (100 mL), washed with water (30 mL), dried over MgSO ₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (95: 5 to 80:20) as eluant to give

4-Bromo-7-phenylisoquinoline colored solid. (389 mg, 1.37 mmol) as a straw ¹ H NMR (δ, CDC1 _3, 300 MHz) 7.4 -7.6 (3H, m), 7.65-7.75 (2H, m), 8.1 (1H, d), 8.15 (1H, S), 8.2 (1H, d), 8.7 (1H, s), 9.2

(1 H, s).

LRMS 283,284,286.

Preparation 3

7-Bromo-1,4-dichloroisoquinoline (i) A solution of 4-bromocinnamic acid (5.03 g, 22.2 mmol) in thionyl chloride (SOCl ₂ ) (15 mL) was stirred at 23 ° C for 16 hours and then Heat at reflux for 2 hours. The solvent was evaporated in vacuo and the residue azeotroped with toluene (3x) to give 4-bromo-cinnamide chloride as an orange-brown solid in quantitative yield.

1 H NMR (δ, CDCl ₃ , 300 MHz) 6.65 (1H, d), 7.4 (2H, d), 7.8 (1H, d).

• 4,444

4 4

4 4 4

4,444 4 • ♦ 4

4

- 52 44 44

4 4 4

4 4 4 4

4 4 4

44 (ii) A solution of sodium azide (NaN ₃ ) (2.2 g, 33.8 mmol) in water (7.5 mL) was added dropwise at -10 ° C to a stirred solution of 4- of cinnamic acid (22.2 mmol) in acetone (22 mL). The heterogeneous mixture was stirred at 0 ° C for 1 hour and diluted with water (25 mL). The precipitate was collected by filtration and dried under vacuum over phosphorus pentoxide (P ₂ O ₅ ) ^and 4-bromocinnamic acid azide (5.22 g, 20.7 mmol) was obtained as a gold-colored solid.

¹ H NMR (δ, CDCl ₃ , 300 MHz) 6.4 (1H, d), 7.4 (2H, d), 7.5 (2H, d), 7.65 (1H, d).

(iii) This stage is highly explosive - be careful and apply protection

A heated solution of 4-bromo-cinnamic azide (5.22 g, 20.7 mmol) in diphenyl ether (Ph ₂ O) (25 mL) was added dropwise at 270 ° C over 15 minutes to stirred Ph ₂ O (10 mL). The mixture was heated at 270 ° C for 1.5 hours, cooled to 23 ° C and then poured into hexanes (400 mL). The precipitate was collected by filtration with hexanes (2 x 100 mL), washed and purified by silica gel column chromatography using hexanes-EtQAc (6: 4 to 100% EtOAc) as eluant to give 7-bromoisoquinolone (1.64 g). (7.3 mmol) as a white solid.

- * - (NMR (δ, DMSO-d6, 300 MHz) 6.55 (1H, d), 7.25-7.15 (1H, m),

7.6 (1H, d), 7.8 (1H, d), 8.25 (1H, s), 11.4 (1H, br s).

(iv) A mixture of 7-bromoisoquinolone (1.28 g, 5.69 mmol) and PCl ₅ (2.04 g, 9.80 mmol) was heated at 140 ° C for 5 hours. The cold mixture was cooled with ice (50 g) and 0.880 ammonia was added to the alkaline reaction (litmus paper). The aqueous mixture was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over MgSO ₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography using hexane-EtOAc (97: 3 to 95: 5) as eluant to give 7-bromo-1,4-dichloroisoquinoline (1.13 g, 4.08 mmol) as a white solid substance.

Mp 133.5-135 ° C.

·· 4444

• 4 • • 4 44 • 4 4444 4

4 4 • 5 «

- 53 • 4 44

4 4 4 4

4 4 4 4

4 4 4 4 4

4 4 4 4

44 4 4 ^1, (δ, CDCl ₃ , 300 MHz) 7.9 (1H, d), 8.1 (1H, d), 8.35 (1H, S), 8.5 (1H, s).

LRMS 276,278 (MH).

Found: C, 39.04; H, 1.32; N, 5.06. Calcd for C ₈ H ₄ BrCl ₂ N: C, 39.03; H, 1.46; N, 5.06.

Preparation 4

6-Bromoisoquinoline N-oxide

Acetic acid (8 mL) and 30% hydrogen peroxide (4 mL) were heated at 80 ° C for 1 hour. A cold peracetic acid solution was added to 6-bromoisoquinoline (Tyson, F.T.J.).

A. Chem. Soc., 1939, 61, 183) (0.389 g, 1.87 mmol) and the mixture was heated at 80 ° C for 18 hours. The mixture was diluted with water (15 mL) and concentrated in vacuo to about half the volume, and the residue was extracted with CH ₂ Cl ₂ . (2x25 mL). The combined organics were washed with saturated aqueous NaHCO ₃ (25 mL), dried over MgSO ₄ and evaporated to an oil. Azeotroping with PhMe (3x) and then CH ₂ Cl ₂ (3x) gave 6-bromoisoquinoline N-oxide (0.420 g, quant.) As a cream colored solid.

¹ H (δ, CDCl ₃ , 300 MHz) 7.6-7.65 (2H, m), 7.77 (1H, dd),

8.0 (1H, s), 8.2 (1H, dd), 8.85 (1H, s).

LRMS 223, 226 (MH &lt; + &gt;).

The following compounds of Preparations 5-8 were prepared in a similar manner.

Preparation 5 (i) 5-Bromoisoquinoline N-Oxide and (ii) 7-Bromoisoquinoline N-Oxide

The title compounds (1: 1 mixture) are prepared from a 1: 1 mixture of 5-bromoisoquinoline and 7-bromoisoquinoline as a white powder. Mp 149-151 ° C.

¹ H NMR (δ, CDCl ₃ , 300 MHz) 7.5 (1H, dd), 7.6-7.7 (4H, m),

4444 • 4 4

4 4 4

4 4 4 • 4 4 4 • 4 4 4

44 • 4 4 * 4 4

4 4 4

44444 44 44 4 4

4 4

4 4

4 4 4 4

7.85 (1 H, d), 7.9 (1H, S), 8.05 (1H, d), 8.1 (1H, dd), 8.2 (1H, dd), 8.7 (1H, s), 8.75 (1 H, S). LRMS 224 (MH)

Preparation 6 (i) 5-Cyanoisoquinoline N-oxide and (ii) 7-Cyanoisoquinoline N-oxide

The title compounds (1: 1 mixture) are prepared from a 1: 1 mixture of 5-cyanoisoquinoline and 7-cyanoisoquinoline (Tyson, F.T.

J. Am. Chem. Soc., 1939, 61, 183) as a pale yellow powder.

¹ H NMR (δ, DMSO-d 6, 300 MHz) 7.8 (1H, dd), 7.85 (1H, d), 8.05 (1H, d), 8.1 (1H, d), 8 15 (1H, s), 8.2 (1H, s), 8.25-8.35 (2H, m), 8.45 (1H, s), 9.0 (1H, s) 9.1 (1 H, s).

LRMS 171 (MH), 341 (M ₂ H).

Preparation 7

4,7-Dibromoisoquinoline N-oxide

The title compound was prepared from 4,7-dibromoisoquinoline.

¹ H (δ, DMSO-d 6, 300 MHz) 7.85 (1H, d), 7.9 (1H, d), 8.25 (1H, s), 8.65 (1H, s), 8, 95 (1 H, s).

LRMS 302, 303, 305, 306 (MH &lt; + &gt;).

Preparation 8

4-Bromo-7-phenylisoquinoline N-oxide

The title compound was prepared from 4-bromo-phenylisoquinoline as a lemon-colored solid.

^{Τ Η} NMR (δ, DMSO-d₆, 300 MHz) 7.4-7.6 (3H, d), 7.75-7.85 (2H, m), 8.05 (2H, s), 8, 25 (1H, s), 8.6 (1H, s), 9.0 (1H, s).

LRMS 299, 301 (MH &lt; + &gt;).

· * · * * * * * ·

9 9 9 9 9 9 * 9999 9 9 9 9 9 9 9 9 9

9 99 9

- 56 · ♦ * ··· Φ · • φ 9 9

9 9 • ♦ * *

The title compound was prepared from 5-benzyloxyisoquinoline (see Japanese patent application JP 51070772) as a yellow solid.

¹ H (δ, CDCl ₃ , 400 MHz) 5.2 (2H, s), 6.95 (1H, d), 7.25 (1H, d), 7 / 3-7.5 (6H, m) 8.1 (2H, s); 8.7 (1H, s).

LRMS 252 (MH &lt; + &gt;).

Preparation 12

5-Phenylisoquinoline N-oxide

The title compound was prepared from 5-phenylisoquinoline (Pridgen, L. N.J. Het. Chem. 1980, 17, 1289) as a yellow viscous oil.

¹ H NMR (δ, DMSO-d 6, 400 MHz) 7.4-7.5 (6H, m), 7.6 (1H, d),

7.7 (1H, dd), 7.9 (1H, d), 8.1 (1H, d), 9.0 (1H, s).

LRMS 222 (MH &lt; + &gt;).

Preparation 13

6- Methylisoquinoline N-oxide

The title compound was prepared from 6-methylisoquinoline (Brown, E.V. Org. Chem. 1977, 42, 3208) as an off-white solid.

¹ H (δ, DMSO-d6, 400 MHz) 2.5 (3H, s), 7.5 (1H, d), 7.7 (1H, S), 7.75-7.85 (2H, m) ), 8.1 (1H, d), 8.85 (1H, s).

LRMS 160 (M), 319 (M ₂ H).

Preparation 14

6,7- (Methylenedioxy) isoquinoline N-oxide

The title compound was prepared from 6,7- (methylenedioxy) isoquinoline (P. Fritsch, Ann. 1895, 286, 1) as a cream.

44 44

4 4 4 4 • 4 4 4 4 4

4 4 4 4

44 44

4

4 4 44

4 4 4 4 4 4 4 4442 4 4 4

4 4 4 4

4 44

- 57 colored solid.

¹ H (5, DMSO-d6, 400 MHz) 6.1 (2H, s), 7.05 (1H, s), 7.15 (1H, s), 7.7 (1H, d), 8, O (1H, d), 8.7 (1H, s).

LRMS 190 (MH), 379 (M ₂ H).

Preparation 15

6-Bromo-1-chloroisoquinoline

Phosphorus oxychloride (0.60 mL, 6.44 mmol) was added in one portion to a stirred solution of 6-Bromo-isoquinoline N-oxide (409 mg, 1.83 mmol) in CH ₂ C1 ₂ (10 ml) and the mixture heated under reflux for 6 hours. Excess solvent was evaporated in vacuo, the residue suspended in water (10 mL) and basified with 0.880 ammonia. This mixture was extracted with CH ₂ Cl ₂ (2 x 25 mL) and the combined organics were dried over MgSO ₄ and evaporated to give the crude product. Purification by column chromatography on silica gel using hexanes-EtOAc (90:10) as eluant gave 6-bromo-1-chloroisoquinoline (215 mg, 0.86 mmol) as a cream colored solid.

Melting point 105-107 ° C.

^Τ Η (δ, CDCl ₃ , 300 MHz) 7.5 (1H, d), 7.75 (1H, dd), 8.05 (1H, d), 8.2 (1H, d), 8.3 (1 H, d).

LRMS 244 (MH &lt; + &gt;).

Elemental analysis: Found C, 44.50; H, 1.98; N, 5.73. Calcd. For C 8 H 9 BrClN: C, 44.58; H, 2.08; N, 5.78.

The compounds of Preparations 16 to 25 below are prepared similarly from the corresponding N-oxides of Preparation 15:

Preparation 16 1-Chloro-5- (ethoxycarbonylmethoxy) isoquinoline

The title compound was prepared from 5- (ethoxycarbonylmethoxy) isoquinoline N-oxide as a white solid.

• · »

to *

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52-54 ° C.

¹ H NMR (δ, CDCl ₃ , 300 MHz) 1.3 (3H, t), 4.3 s), 7.0 (1H, d), 7.65 (1H, dd), 7.9 (1H d) (lH, d).

LRMS 265 (MH &lt; + &gt;).

(2H, q), 4.8 (2H, 8.1 (1H, d), 8.3)

Found: C, 58.70; H, 4.48; N, 5.18. Calcd. For C 1 H 11 Cl 2 Cl 2: C, 58.77; H, 4.48; N, 5.18.

Preparation 17

5-Benzyloxy-1-chloroisoquinoline

The title compound was prepared from 5-benzyloxyisoquinoline N-oxide as a white solid.

Melting point 95-96 ° C.

¹ H (δ, CDCl ₃ , 300 MHz) 5.2 (2H, s), 7.1 (1H, d), 7.3-7.5 (5H, m), 7.55 (1H, dd) 7.85 (1H, d), 8.0 (1H, d), 8.2 (1H, d).

LRMS 270, 272 (MH &lt; + &gt;).

Found: C, 71.18; H, 4.43; N, 5.09. Calculated for C ₁₆ H ₁₂ ^{C1NO: C} '71.25; H, 4.48; N, 5.19.

Preparation 18 1-Chloro-5-phenylisoquinoline

The title compound was prepared from 5-phenylisoquinoline N-oxide as an oil.

1 H NMR (δ, CDCl ₃ , 400 MHz) 7.35-7.55 (5H, m), 7.6-7.75 (3H, m), 8.2 (1H, d), 8.35 ( 1 H, d).

LRMS 240, 242 (MH &lt; + &gt;).

Found: C, 74.66; 4,1, 4.17; N, 5.81. Calcd for C ₁₅ H ₁₀ ClN + 0.1 H ₂ O: C, 74.66; H, 4.26; N, 5.80.

Preparation 19 «

- 58 44 4

4 4 4 4

4444 4

4

4

4

4 4

4 4

4

4 4 4

4 4 «

4 4 4 4

4 4 4

44

1-Chloro-6-methylisoquinoline

The title compound was prepared from 6-methyleneisoquinoline N-oxide as a straw colored solid.

¹ H (δ, CDCl ₃ , 300 MHz) 2.6 (3H, s), 7.45-7.6 (2H, m), 7.6 (1H, s), 8.2-8.3 ( 2H, m).

LRMS 178, 180 (MH &lt; + &gt;).

Preparation 20

7-Bromo-1-isoquinoline

The title compound was prepared from a mixture of 5- and 7-bromoisoquinoline N-oxides and separated from 5-bromo-1-chloroisoquinoline by chromatography to give a white solid.

¹ H NMR (δ, CDCl ₃ , 300 MHz) 7.5 (1H, d), 7.7 (1H, d), 7.8 (1H, d), 8.3 (1H, d), 8, Δ (1H, s).

LRMS 244,246 (MH).

Preparation 21 1-Chloro-7-cyanoisoquinoline

The title compound was prepared from a mixture of 5- and 7-cyanoisoquinoline N-oxides and separated from 1-chloro-5-cyanoisoquinoline by chromatography to give a white powder.

^Χ Η (δ, CDCl ₃ , 400 MHz) 7.7 (1H, d), 7.9 (1H, d), 7.95 (1H, d), 8.45 (1H, d), 8.75 (1 H, s).

LRMS 189 (MH &lt; + &gt;).

Example 22

7-Benzyloxy-1-chloroquinoline

The title compound was prepared from 7-benzylisoquinoline N-oxide as a white powder.

· * · • • • • • • •>>>>>>>>>>>>> * * * · · · · · · · · · · ·

M.p. 128-131 ° C.

¹ H NMR (δ, CDCl ₃ , 400 MHz) 5.2 (2H, s), 7.3-7.5 (7H, m), 7.65 (1H, s), 7.75 (1H, d) 8.35 (1 H, d).

LRMS 270, 272 (MH &lt; + &gt;).

Found: C, 71.04; H, 4.47; N, 5.12. Calculated for C ₁₆ H ₁₂ C1NO: C, 71.25; H, 4.48; N, 5.19.

Preparation 23 1-Chloro-4,7-dibromoisoquinoline

The title compound was prepared from 4,7-dibromoisoquinoline N-oxide as a white solid.

¹ H (δ, CDCl ₃ , 400 MHz) 7.9 (1H, dd), 8.05 (1H, d), 8.45 (1H, S), 8.5 (1H, d).

LRMS 321 (MH &lt; + &gt;).

Preparation 24

4-Bromo-1-chloro-7-phenylisoquinoline

The title compound was prepared from 4-bromo-7-phenylisoquinoline N-oxide as a white solid.

Mp 144-147 ° C.

¹ H (δ, CDCl ₃ , 300 MHz) 7.4-7.6 (3H, m), 7.7-7.75 (2H, m),

8.1 (1H, d), 8.25 (1H, d), 8.45 (1H, s), 8.5 (1H, s).

LRMS 321 (MH &lt; + &gt;).

Found: C, 56.71; H, 2.89; N, 4.30. Calcd for C 1 H 11 BrClN: C, 56.55; H, 2.85; N, 4.40.

Preparation 25 1-Chloro-6,7- (methylenedioxy) isoquinoline

The title compound was prepared from 6,7- (methylenedioxy) isoquinoline N-oxide as a cream solid.

• ·

4 44 • 4444

4 »445«

4 4

4 4 4 4

4 4 4 4

4 4 4 4

44 44 ¹ H NMR (δ, CDCl ₃ , 300MHz) 6.15 (2H, s), 7.05 (1H, s), 7.4 (1H, d), 7.6 (1H, S), 8 1 (1 H, d).

LRMS 207, 210 (MH &lt; + &gt;).

Preparation 26

3,5-Dimethoxyphenylboronic acid

To 1-bromo-3,5-dimethoxybenzene (1.4 g, 6.45 mmol) (Dean, N. B .; Whalley, WBJ Chem. Soc. 1954, 4638) in THF (60 mL) was added under nitrogen at -70 ° C n-BuLi (2.6 mL, 2.5 M in hexanes). After 10 minutes, the clear yellow solution was treated with trimethylborate (1.5 mL, 13.2 mmol) in THF (2 mL) and stirred for an additional hour, then allowed to warm to room temperature over 3 hours and allowed to cool with water (10 mL). ml). After dilution with water (50 mL), the mixture was extracted with methylene chloride (2x). The combined organics were washed with brine and concentrated to give an off-white solid, which was recrystallized from diethyl ether to give a white solid (400 mg, 2.2 mmol).

Mp 195-197 ° C.

¹ H NMR (δ, DMSO-d 6, 300 MHz) 3.7 (3H, s), 3.75 (3H, s), 6.45-6.5 (1H, m), 6.85-6, 95 (2 H, m).

LRMS 183 (MH &lt; + &gt;).

Preparation 27

1,4-Dichloro-7- (4-methylphenyl) isoquinoline

A mixture of 7-bromo-1,4-dichloroisoquinoline (276 mg, 1.0 mmol), tetrakis (trifebnylphosphine) palladium (0) (60 mg, 5 mol%),

4-methylphenylboronic acid (137 mg, 1.0 mmol) and aqueous Na ₂ CO ₃ (2.0 mL, 1.0 M, 2.0 mmol) in DME (6 mL) was heated to reflux under N ₂ 20 hours. The mixture was diluted with EtOAc (100 mL), washed with water (30 mL), dried over MgSO ₄ and evaporated in vacuo. The residue was purified by column chromatography to 4440 <

4 4 4 · 4 4

4 4 4 4

4 44

- 62 44 44

4 4 4 4

4 4 4 4

4 4 4 4 4

4 4 4 4

Silica gel using hexanes-EtOAc (99: 1 to 97: 3) as eluant gave 1,4-dichloro-7- (4-methylphenyl) isoquinoline (139 mg, 0.48 mmol) as a solid.

¹ H (δ, CDCl ₃ , 300 MHz) 2.45 (3H, s), 7.35 (2H, d), 7.65 (2H, d), 8.1 (1H, dd), 8.25 (1H, d), 8.3 (1H, s), 8.5 (1H, d).

LRMS 288,290,292 (MH).

The following compounds of Preparations 28-41 were prepared in a similar manner.

Preparation 28 1-Chloro-7-phenylisoquinoline

The title compound was prepared from 7-bromo-1-chloroisoquinoline and phenylboronic acid as an oil.

¹ H (δ, CDCl ₃ , 400 MHz) 7.4-7.55 (3H, m), 7.65 (1H, d), 7.75 (2 H, d), 7.9 (1H, d), 8.05 (1H, d), 8.3 (1H, d), 8.55 (1 H, S). LRMS 240

Preparation 29 1-Chloro-7- (3,4-methylenedioxyphenyl) isoquinoline

The title compound was prepared from 7-bromo-1-chloroisoquinoline and 3,4-methylenedioxyphenylboronic acid (Banwell, M. G.; Cowden, C. J. Aust. J. Chem. 1994, 47, 2235) as a white powder.

¹ H (δ, CDCl ₃ , 400 MHz) 6.1 (2H, s), 7.05 (1H, d), 7.3 (1H, d), 7.4 (1H, S), 7.9 (1H, d), 8.1 (1H, d), 8.15 (1H, d),

8.25 (1 H, d), 8.3 (1 H, s).

LRMS 284, 286 (MH &lt; + &gt;).

Found: C, 67.54; H, 3.51; N, 4.87. Calcd for C ₁₆ H ₁₀ ClNO ₂ : C, 67.74; H, 3.55; N, 4.94.

· «• · · · · · · · · ·

- 63 ’β β 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

99 99

Preparation 30

7- (2-Benzofuranyl) -1,4-dihydroisquinoline

The title compound was prepared from 7-bromo-1,4-dichloro-isoquinoline and benzo [b] furan-2-boronic acid as a yellow solid.

Melting point 162 ° C.

(δ, CDCl ₃ , 400 MHz) 7.25-7.3 (2H, m), 7.3 (1, dd), 7.55-7.65 (2H, m), 8.25 (2H, m, d), 8.3 (1H, d), 8.75 (1H, s). LRMS 316 (MH &lt; + &gt;).

Found: C, 62.93; H, 2.79, N, 4.33. Found for C ₁₇ H ₉ Cl ₂ NO: C, 63.21; H, 2.97; N, 4.32.

Preparation 31

1,4-Dichloro-7- (3-thienyl) isoquinoline

The title compound was prepared from 7-bromo-1,4-dichloro-isoquinoline and thiophene-3-boronic acid as a yellow solid.

Melting point 109 ° C.

¹ H (δ, CDCl ₃ , 400 MHz) 7.45 (1H, d), * 7.5 (1H, d), 7.7 (1H, S), 8.1 (1H, d), 8, 2 (1 H, d), 8.3 (1 H, s), 8.45 (1 H, s)

LRMS 280,282 (MH).

Preparation 32

1,4-Dichloro-7- (2-methoxyphenyl) isoquinoline

The title compound was prepared from 7-bromo-1,4-dichloroisoquinoline and 2-methoxyphenylboronic acid as a light cream solid.

¹ H (δ, CDCl ₃ , 400 MHz) 3.8 (3H, s), 7.05 (1H, d), 7.1 (H, dd), 7.35-7.45 (2H, m) 8.05 (1H, d), 8.2 (1H, d), 8.3 (1H, t 4444)

4 4 · 4 · 4 · 4 · 4

• · 4

4 4

4

S), 8.4 (1H, s).

LRMS 304, 306 (MH &lt; + &gt;).

Preparation 33

1,4-Dichloro-7- (3-methoxyphenyl) isoquinoline

The title compound was prepared from 7-bromo-1,4-dichloroisoquinolines and 3-methoxyphenylboronic acid as a pale yellow cream solid.

* · Η (δ, CDCl ₃ , 300 MHz) 3.95 (3H, s), 7.0 (1H, d), 7.25 (1H, S), 7.3 (1H, d), 7, 45 (1H, dd), 8.1 (1H, dd), 8.25 (1H, d), 8.35 (1H, s), 8.5 (1H, s).

LRMS 304, 306, 308 (MH &lt; + &gt;).

Preparation 34

1,4-Dichloro-7- (4-methoxyphenyl) isoquinoline

The title compound was prepared from 7-bromo-1,4-dihydroisoquinolines and 4-methoxyphenylboronic acid as a pale yellow solid.

Melting point 124-126 ° C.

² H (δ, CDCl ₃ , 4.00 MHz) 3.9 (3H, s), 7.05 (2H, d), 7.7 (2H, d), 8.1 (1H, d), 8.25 (1 H, d), 8.3 (1 H, s), 8.45 (1 H,

S).

LRMS 304, 306, 308 (MH &lt; + &gt;).

Found: C, 62.28; H, 3.56; N, 4.46. Calculated for C ₁ gH ₁₁ Cl ₂ NO + 0.05 CH ₂ C1 _2: C, 62.50; H, 3.63; N, 4.54.

Preparation 35

1,4-Dichloro-7- (3,4-methylenedioxyphenyl) isoquinoline

The title compound was prepared from 7-bromo-1,4-dichloroisoquinoline and 3,4-methylenedioxyphenylboronic acid as a solid.

¹ H (δ, DMSO-d6, 300 MHz) 6.1 (2H, s), 7.1 (1H, d), 7.35 (1H, d), 7.45 (1H, S), 8, 25 (1 H, d), 8.35 (1 H, d), 8.4 (1 H,

S), 8.45 (1H, s).

LRMS 318.320 (MH).

Preparation 36

1,4-Dichloro-7- (3,5-dimethoxyphenyl) isoquinoline

The title compound was prepared from 7-bromo-1,4-dichloroisoquinoline and 3,5-dimethoxyphenylboronic acid as an off-white solid.

Melting point 140-142 ° C.

^ΔΧ (δ, CDCl ₃ , 400 MHz) 3.85 (6H, s), 6.55 (1H, s), 6.8 (2H, s), 8.1 (1H, d), 8.25 (1H, d), 8.3 (1H, s), 8.5 (1H, s).

LRMS 333, 335, 337 (MH &lt; + &gt;).

Found: C, 61.17; H, 4.05; N, 3.78. Calcd. For 0 ₁₇ Η ₁₃ 01 _{2 2 0} + 0.14 EtOAc: C, 60.86; H, 4.11;

N, 4.04.

Preparation 37

7- (3-Cyanophenyl) -1,4-dichloroisoquinoline

The title compound was prepared in a similar manner to Preparation 42 from 7-bromo-1,4-dichloroisoquinoline and 3-cyanophenylboronic acid (International Patent Application WO 94/11372) to give a white solid.

Melting point 197-199 ° C.

¹ H NMR (δ, CDCl ₃ , 300 MHz) 8.5 (1H, s), 8.4 (1H, s), 8.3 (1H, d), 8.1 (1H, d), 8, O (1H, s), 7.95 (1H, d), 7.7 (1H, d), 7.65 (1H, d).

LRMS 298, 300.

Found: C, 64.01; H, 2.67; N, 9.20.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- Calculated for C 66 ₁ gHgCl ₂ N ^{_2: C; 64,} 24; H, 2.70; N, 9.36.

Preparation 38

4-Bromo-1-chloro-7- (3-chlorophenyl) isoquinoline

The title compound was prepared in a manner analogous to Preparation 42, starting from 1-chloro-4,7-dibromoisoquinoline and 3-chlorophenylboronic acid as a white solid.

Melting point 140-142 ° C.

¹ H (δ, CDCl ₃ , 300 MHz) 7.4-7.55 (2H, m), 7.6 (1H, d),

7.75 (1H, s), 8.1 (1H, d), 8.3 (1H, d), 8.5 (2H, s).

LRMS 352, 354, 356 (MH &lt; + &gt;).

Found: C, 50.38; H, 2.20; N, 3.93. Calcd for C ₁₅ H ₉ BrCl ₂ N: C, 50.60; H, 2.33; N, 3.93.

Preparation 39

4-Bromo-1-chloro-7- (4-methylphenyl) isoquinoline

The title compound was prepared in a manner similar to Preparation 42 starting from 1-chloro-4,7-dibromoisoquinoline and 4-methylphenylboronic acid as a solid.

Melting point 108-110 ° C.

¹ H (δ, CDCl ₃ , 400 MHz) 2.4 (3H, s), 7.3 (2H, d), 7.6 (2H, d), 8.1 (1H, d), 8.2 (1H, d), 8.4 (1H, s), 8.45 (1H, s).

LRMS 332, 334, 336 (MH &lt; + &gt;).

Preparation 40

4-Bromo-1-chloro-7- (4-methoxyphenyl) isoquinoline

The title compound was prepared in a manner analogous to Preparation 42 starting from 1-chloro-4,7-dibromoisoquinoline and 4-methoxyphenylboronic acid as a white solid.

Mp 94-96 ° C.

¹ Η (δ, CDCl ₃ , 400 MHz) 3.85 (2H, d), 8.05 (1H, d), 8.15 LRMS 348, 350, 352 (MH +) ).

(3H, s), 7.0 (1H, d), 8.4 (2H, d), 7.65 (2H, s).

Found: C, 55.16; H, 3.13; N, 4.02. Calculated for C ₁ gH ₁₁ BrClNO: C, 55.12; H, 3.18; N, 4.02.

Preparation 41

4-Bromo-1-chloro-7- (3-methoxyphenyl) isoquinoline

The title compound was prepared in a manner analogous to Preparation 42 starting from 1-chloro-4,7-dibromoisoquinoline and 3-methoxyphenylboronic acid as a white solid.

¹ H (δ, CDCl ₃ , 400 MHz) 3.9 (3H, s), 6.9-7.05 (2H, m), 7.3 (1H, d), 7.4 (1H, d) 8.1 (1H, d), 8.2 (1H, d), 8.45 (1H, s), 8.5 (1H, S).

LRMS 347,349,351 (MH).

Found: C, 55.49; H, 3.20; N, 3.94. Calcd for C 18 H 16 BrClNO: C, 55.12; H, 3.18; N, 4.02.

Preparation 42

1,4-Dichloro-7- (2,6-dimethoxyphenyl) isoquinoline

A solution of 7-bromo-1,4-dichloroisoquinoline (396 mg, 1.42 mmol) and 2,6-dimethylboronic acid (261 mg, 1.43 mmol) (J. Chem. Soc. Chem. Commun. 1995, 1085) in anhydrous DME (10 mL) was treated with tetrakis (triphenylphosphine) palladium (0) (38 mg, 19 mol%) and cesium fluoride (485 mg, 3.19 mmol) and the resulting mixture was heated to reflux under N ₂ for for 16 hours. The reaction mixture was cooled to room temperature, partitioned between EtOAc (35 mL) and water (10 mL), dried and evaporated to dryness to give a solid which was purified by silica gel column chromatography using hexanes-EtOAc (99). The solvent was removed in vacuo to afford the title compound as an off-white solid (120.6 mg, 0.36 mmol).

· · · · · · · · · · · · (1H, s), 8.3 (1H, s), 8.2 (1H, t), 6.7 (2H, d), 3.75 (6H, ^{Χ Η} (fi, CDC1 _3, 300 MHz) 8.35 (1H, d), 7.85 (1H, d), _f 7.35).

LRMS 334, 336, 338 (MH &lt; + &gt;).

Preparation 43 1-Chloro-7- (2-phenyl-E-ethenyl) isoquinoline

A solution of 7-bromo-1-chloroisoquinoline (200 mg, 0.80 mmol), styrene (94 mg, 0.90 mmol), tri-o-tolylphosphine (30 mg, 12 mol%) palladium acetate (Pd (OAc) ₂ ) (10 mg, 5 mol%) and triethylamine (0.34 mL, 2.5 mmol) in DMF were placed in MOS-2000 ™ (650 W) and treated with microwaves and irradiation at 7x40s (reaction monitored) TLC). The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , evaporated in vacuo and the residue purified by silica gel column chromatography using hexane-EtOAc (100: 0 to 95: 5) as eluant to give 1-chloro- (2-phenylethylene-). 1-yl) isoquinoline (135 mg, 0.508 mmol) as a yellow solid.

Melting point 118-121 ° C.

¹ H (δ, CDCl ₃ , 300 MHz), 7.3-7.35 (3H, m), 7.44 (2H, dd), 7.55-7.65 (3H, m), 7, Δ (1H, d), 8.0 (1H, d), 8.25 (1H, d),

8.3 (1 H, s).

LRMS 266, 268 (MH &lt; + &gt;).

Elemental analysis calculated: C, 76.87; H, 4.61; N, 5.18. Calculated for C ₁₇ H ₁₂ C1N: C, 76.84; H, 4.55; N, 5.27.

Preparation 44

1-Chloro-5-isoquinolinecarboxaldehyde

A solution of n-BuLi (1.76 mL, 2.5 M in hexanes, 4.4 mmol) was added at -78 ° C under N ₂ to a stirred solution of 5-bromo-1-chloroisoquinoline (Braye, E., Eloy) Hoogzand, C .; Lenaers, R. Eur. J. Med.

φ φ φ φφ φ φφ ·

Φ Φ Φ · 9 Φ

• Φ Φ • • • · • ••••• Φ * Φ Φ

Φ Φ · Φ Φ Φ

- 69 Chem., Chim. Therap. 1974, 9, 197) (1.0 g, 4.12 mmol) in THF-ether (36 mL, 1: 1). After 20 min, DMF (0.66 mL, 8.5 mmol) was added and after an additional 30 min at -78 ° C, the reaction mixture was cooled with EtOH (3 mL) and warmed to room temperature. The mixture was diluted with ether (150 mL), washed with saturated NH ₄ Cl (50 mL), brine, dried over MgSO ₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (95: 5 to 50:50) as eluant to give 1-chloro-5-isoquinolinecarboxaldehyde (308 mg, 1.61 mmol) as a white solid.

¹ H (δ, CDCl ₃ , 400 MHz) 7.9 (1H, d), 8.5 (1H, d), 8.7 (1H, d), 9.0 (1H, d), 10.4 (1 H, s).

LRMS 192, 194 (MH &lt; + &gt;).

Preparation 45 1-Chloro-7-isoquinolinecarboxaldehyde

The title compound was prepared in a manner similar to Preparation 44 from 7-bromo-1-chloroisoquinoline as a white solid.

¹ H (δ, DMSO-d6, 300 MHz) 7.95 (1H, d), 8.2 (2H, s), 8.4 (1H, d), 8.85 (1H, s), 10, 2 (1 H, s).

LRMS 192, 194 (MH &lt; + &gt;).

Preparation 46

7-Carboxy-1-chloroisoquinoline hydrochloride

A solution of n-BuLi (1.2 mL, 2.5 M in hexanes, 3.0 mmol) was added dropwise at -78 ° C under N ₂ to a stirred solution of 7-bromo-1-chloroisoquinoline (0.64 g, 2.64 mmol) in THF (10 mL) and ether (10 mL). After 20 minutes, crushed CO ₂ (excess) was added in one portion and allowed to warm to room temperature. The solvents were evaporated in vacuo and the residue was partitioned between aqueous NaOH (20 mL, 0.5 M) and ether (50 mL). The aqueous phase is acidified with conc. HCl, extracted with EtOAc (3 x 50 mL) and the combined organic extracts dried over MgSO ₄ and evaporated to give 7-carboxy-1-chloroisoquinoline hydrochloride (0.277 g, 1.13 mmol) as an off-white solid.

^{Χ Η} (δ, DMSO-d₆, 300 MHz) 7.95 (1H, d), 8.15 (1H, d), 8.3 (1H, d), 8.3 (1H, d), 8, Δ (1H, d), 8.8 (1H, s), 13.5 (1H, br s). LRMS 208, 210 (M + H).

Preparation 47 1-Chloro-7- (1-hydroxycyclohex-1-yl) isoquinoline

A solution of 7-bromo-1-chloroisoquinoline (200 mg, 0.82 mmol) and anhydrous THF (4 mL) was treated at -78 ° C with BuLi (1.3 M in cyclohexane, 0.7 mL, 0.91 mmol) ) to give a dark green solution, which was cooled after 4 minutes with cyclohexanone (100 mL, 0.96 mmol). Remove the cooling bath and allow the reaction mixture to warm to ambient temperature, stir for 20 minutes and cool with a drop of water. THF was removed in vacuo and water was added to the residue, which was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL) and then dried over MgSO ₄ and condensed on silica gel (1 g) and purified by column chromatography (silica gel, 15 g) using hexanes-EtOAc ( 100: 15 to 100: 20) as eluant to give the title compound as a white solid (83 mg, 0.32 mmol).

Melting point 109.5-111 ° C.

^Χ Η (δ, CDCl ₃ , 300 MHz) 1.3-2.1 (11H, m), 7.55 (1H, d), 7.85 (1H, d), 7.95 (1H, d) 8.25 (1H, d); 8.45 (1H, s).

LRMS 262,264 (MH).

The following compounds of Preparations 48-51 were prepared in a similar manner:

Preparation 48

9 9

9

9 9999

9999 99

9 9 9 9 ·

9

9 9 9 9 9

9 9 9

99

9 99 9 1-Chloro-7- (1-hydroxycyclopent-1-yl) isoquinoline

The title compound was prepared from 7-bromo-1-chloroisoquinoline by cooling the formed anion with cyclopentanone to give a yellow solid.

¹ H (δ, CDCl ₃ , 300 MHz) 1.5-2.2 (9H, m), 7.6 (1H, d), 7.8 (1H, d), 8.25 (1H, d) 8.45 (1 H, s).

LRMS 248, 250 (MH &lt; + &gt;).

Preparation 49 1-Chloro-7- (1-hydroxy-1-phenylethyl) isoquinoline

The title compound is prepared from 7-bromo-1-chloroisoquinoline by cooling the formed anion with acetophenone to give a cream solid.

Melting point 134-135 ° C.

¹ H (δ, CDCl ₃ , 400 MHz) 2.0 (3H, m), 2.3 (1H, br s), 7.2-7.35 (3H, m), 7.35-7.45 (2H, m), 7.5 (1H, d), 7.65 (1H, d), 7.7 (1H, d), 8.2 (1H, d), 8.45 (1H, s) .

LRMS 284, 286 (MH &lt; + &gt;).

Found: C, 71.49; H, 5.06; N, 4.90. Calcd. For C ₁₇ H ₁₄ ClNO + 0.08 EtOAc: C, 71.54; H, 5.07; N, 4.82.

Preparation 50 1-Chloro-7- (α-hydroxybenzyl) isoquinoline

The title compound was prepared from 7-bromo-1-chloroisoquinoline by cooling the formed anion with benzaldehyde to give a white solid.

^ΔΧ (δ, CDCl ₃ , 300 MHz) 2.45 (1H, d), 6.05 (1H, d), 7.2-7.45 (5H, m), 7.55 (1H, d) 7.7 (1H, d), 7.75 (1H, d), 8.15 (1H, d), 8.4 (1H, s)

LRMS 270, 272 (MH &lt; + &gt;).

This to this this to this this to this this to this this ·· ·· to ·· · ·· ··

- 72 Elemental analysis - found: C, 70.11; H, 4.63; N, 4.85. Calcd for C 18 H 18 Cl 2 N + 0.2 EtOAc: C, 70.22; H, 4.77; N,

4.87.

Example 51

The title compound was prepared from 7-bromo-1,4-dichloroisoquinoline by cooling the formed anion with benzaldehyde to give a white solid.

mp 121-122 ° C.

¹ H (δ, CDCl ₃ , 300 MHz) 2.3-2.6 (1H, br s), 6.1 (1H, s),

7.25-7.5 (5H, m), 7.85 (1H, d), 8.15 (1H, d), 8.3 (1H, s),

8.45 (1 H, S).

LRMS 304, 306 (MH &lt; + &gt;).

Found: C, 62.55; H, 3.45; N, 4.61. Calcd for C ₁₆ H ₁₁ Cl ₂ NO + 0.2 water: C, 62.44; H, 3.73; N, 4.55.

Preparation 52 1-Chloro-7- (1-hydroxyethyl) isoquinoline

A slurry of 1-chloro-7-isoquinolinecarboxaldehyde (148 mg, 0.78 mmol) in anhydrous THF (8 mL) at -78 ° C was treated with MeLi (1.0 M in THF, 0.86 mL, 0.86 mmol). ) 30 minutes. After 15 minutes the solution was warmed to 0 ° C and stirred for an additional 1 hour. The reaction mixture was then diluted with EtOAc (30 mL), washed with saturated ammonium chloride solution (20 mL), brine (20 mL), dried over MgSO _4, and condensed to an orange-brown oil. Purification by silica gel column chromatography (25 g) using hexanes-EtOAc (10: 3) as eluant gave the title compound as an off-white oil (85 mg, 0.41 mmol).

1 H (δ, CDCl ₃ , 400 MHz) 1.55 (3H, d), 2.15 (1H, s), 5.1 (1H, q), 7.55 (1H, d), 7.7 -7.8 (2H, m), 8.2 (1H, d), 8.25 (1H, d). LRMS 208, 210 (MH &lt; + &gt;).

4 4

4 «44

4 4 4

4444444 4

4 4 4 4

4 4 4

4 «4444

4 * 44

4 4 4 4

4 4 4 4 4

4 4 4 4

4 4 · ·

- 73 Preparation 53

1-Chloro-5-hydroxymethylisoquinoline

A solution of 1-chloro-5-isoquinolinecarboxaldehyde (308 mg, 1.6 mmol) and sodium borohydride (NaBH ₄ ) (68 mg, 1.8 mmol) in MeOH (6 mL) was stirred at room temperature for 2 hours. The reaction mixture was cooled with water (2 mL) and concentrated in vacuo. The residue was suspended in CH ₂ C1 _2, washed with water, brine and then dried over MgSO ₄ and evaporated. The residue was purified by silica gel column chromatography using hexanes-EtOAc (80:20 to 50:50) as eluant to give 1-chloro-5- (hydroxymethyl) isoquinoline (240 mg, 1.23 mmol) as a white solid . ^Χ Η (δ, CDCl ₃ , 400 MHz) 2.0 (1H, br s), 5.15 (1H, s), 7.7 (1H, dd), 7.8 (1H, d), 7, Δ (1H, d), 8.35 (2H, m).

LRMS 193 (MH), 387 (M ₂ H).

Preparation 54 1-Chloro-7-hydroxymethylisoquinoline

The title compound was prepared in a manner similar to Preparation 53 from 1-chloroisoquinoline-7-carboxaldehyde to give a white powder.

Melting point 118-121 ° C.

1 H-δ (δ, DMSO-d 6, 300 MHz) 4.7 (2H, d), 5.5 (1H, t), 7.8 (1H, d), 7.85 (1H, d), 8 O (1H, d), 8.2 (1H, s), 8.25 (1H, d).

LRMS 194,196 (MH).

Found: C, 62.24; H, 4.34; N, 7.01. Calcd for C ₁₀ H ₈ ClNO: C, 62.01; H, 4.16; N, 7.23.

Preparation 55

1-Chloro-7-chloromethylisoquinoline hydrochloride

1-Chloro-7- (hydroxymethyl) isoquinoline (510 mg, 2.63 mmol) was added

Φ φ φ φ φ • φφφφ φ φ φ

Add slowly to thionyl chloride (4 ml) at room temperature and stir the mixture slowly at room temperature. is stirred for 1.5 hours to give a complete solution. The thionyl chloride was removed in vacuo and methylene chloride (20 mL) was added. The resulting white powder was removed by filtration and washed with additional methylene chloride (20 mL) and then dried in vacuo to give the title compound (400 mg, 1.61 mmol). A second portion (112 mg, 0.45 mmol) was obtained by evaporation of methylene chloride and trituration with ether / methylene chloride.

Melting point 138-140 ° C.

¹ H (δ, DMSO-d6, 300 MHz) 5.0 (2H, s), 7.8-7.95 (2H, m), 8.05 (1H, d), 8.25-8.35 (2H, m). Elemental analysis - found: C,

47.98; H, 3.17; N, 5.58. Calcd for C ₁₀ H ₈ Cl ₃ N: C, 48.32;

H, 3.24; N, 5.64.

Preparation 56 1-Chloro-7 - [(2-methyl-1H-imidazol-1-yl) methyl] isoquinoline

Sodium hydride (60% dispersion in oil, 48 mg, 1.2 mmol) was added to a solution of 2-methylimidazole (100 mg, 1.2 mmol) in dry DMF (2 mL) and the mixture was stirred at hydrogen temperature until it ceased - evolution of H ₂ and then 1-chloro-7- (chloromethyl) isoquinoline hydrochloride salt (150 mg, 0.6 mmol) was added. The reaction mixture was stirred for 3 hours, poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried over MgSO ₄ and condensed to an oil which was taken up in diisopropyl ether and allowed to crystallize. The solid was removed by filtration to give white crystals of the title compound (70 mg, 0.27 mmol). Next part of the product

mg, 0.27 mmol) is added obtained by concentration of mother of lye. ! η (δ, CDCl ₃ , 400 MHz) 2.35 (3H, s) 5.2 (2H, s), 6.85 (1H, s), 7.95 (1H, s), 7.35 (1 H, d), 7.55 (1 H, d), 7.8 (1H, d), 8.0 (1H, s), 8.15 (1 H, d).

LRMS 258,260 (MH).

Found: C, 65.14; H, 4.66; N, 16.28.

• 4 • 44 • 44

4 4 ·

4 4 4 4

- 75 Calculated for C ₁₄ H ₁₂ ClN ₃ : C, 65.24; H, 4.69; N, 16.31.

Preparation compounds 57 and 58 are prepared in a similar manner:

Preparation 57 1-Chloro-7 - [(2-methyl-ΙΗ-benzo [d] imidazol-1-yl) methyl] isoquinoline

The title compound was prepared from 2-methylbenzimidazole to give a cream solid.

Mp 245-247 ° C.

¹ H (δ, CDCl ₃ , 400MHz) 2.6 (3H, s), 6.6 (2H, s), 7.1-7.25 (3H, m), 7.3 (1H, d), 7.5 (1H, d), 7.7-7.8 (2H, m), 8.15 (1H, s), 8.25 (1H, d).

LRMS 308, 310 (MH &lt; + &gt;).

Found: C, 70.16; H, 4.55; N, 13.54. Calcd for C 14 H 16 ClN 3: C, 70.24; H, 4.59; N, 13.65.

Preparation 58:

1-Chloro-7- (phenoxymethyl) isoquinoline

The title compound was prepared from phenol and the off-white material was used without further purification.

Melting point <60 ° C.

LRMS 270, 272 (MH &lt; + &gt;).

Preparation 59

5-Carboxy-1-chloroisoquinoline hydrochloride

A solution of 5-carbethoxy-1-chloroisoquinoline (patent DE 2816863) (1.75 g, 7.4 mmol) and NaOH (0.8 g, 20 mmol) in MeOH-H ₂ O (50 mL, 4: 1) was added. Stir at 23 ° C for 5 hours. The solvents were evaporated in vacuo and the residue partitioned between CH ₂ C1 ₂ and aqueous NaOH · «· • • 9 9 9 9 9

. 9 9999 9

9 9

9

9999

9 9

9 9

9 9

9 9

9

9

9

9

9

- 76 (2). The aqueous phase is acidified with conc. HCl, extracted with excess EtOAc (4x). The combined organics were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give 5-carboxy-1-chloroisoquinoline hydrochloride (1.8 g, 7.4 mmol) as a white solid.

¹ H (δ, DMSO-d6, 300 MHz) 7.8 (1H, dd), 8.4 (1H, d), 8.5 (1H, d), 8.6 (1H, d), 8, Δ (1H, d), 13.6 (1H, br s).

LRMS 208, 210 (MH &lt; + &gt;).

Preparation 60

5-Carboxymethoxy-1-chloroisoquinoline hydrochloride

The title compound was prepared in a manner similar to Preparation 59 from 5- (ethoxycarbonylmethoxy) -1-chloroisoquinoline to give a white solid.

Melting point > 200 ° C.

* Ή (δ, DMSO-d6, 300 MHz) 4.9 (2H, s), 7.2 (1H, d), 7.7 (1H, dd), 7.8 (1H, d), 8, O (1H, d), 8.3 (1H, d), 12.6 (1H, br s). LRMS 238 (MH &lt; + &gt;).

Preparation 61

5-Carboxamido-1-chloroisoquinoline

A solution of 5-carboxy-1-chloroisoquinoline hydrochloride (395 mg, 1.62 mmol) in SOCl 2 (5 mL) containing DMF (1 drop) was heated at reflux under N ₂ for 2 hours. The solvents were evaporated in vacuo and the residue azeotroped with PhMe to give 1-chloro-5-isoquinoyl chloride hydrochloride (1.62 mmol) as an off-white solid. The acid chloride was used immediately without further purification or characterization.

A solution of 1-chloro-5-isoquinoyl chloride hydrochloride (1.62 mmol) in NH ₃ saturated CH ₂ Cl ₂ (25 mL) was stirred at 23 ° C for 18 hours. The solvent is evaporated off under vacuum and the residue is again evaporated to vacuum. · ····· to · · · · · to · to ··· this ^:

- 77 dissolved in CH ₂ C1 ₂ and washed with water and brine. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a crude product which was purified by trituration with ether to give 5-carboxamido-1-chloroisoquinoline (92 mg, 0.45 mmol) as a white solid.

¹ H (δ, DMSO-d6, 400 MHz) 7.7 (1H, br s), 7.8 (1H, dd), 8.0 (1H, d), 8.1 (1H, br S), 8.2 (1H, d), 8.3 (1H, d), 8.4 (1H, d).

LRMS 206, 209 (MH &lt; + &gt;).

Found: C, 57.61; H, 33; N, 13.30. Calcd for C ₆ H ₇ ClN ₂ O + 0.04CH ₂ Cl ₂ : C, 57.42; H, 3.40; N, 13.34.

The compounds of Preparations 62 and 63 are prepared in a similar manner:

Preparation 62

5- (Carbamoylmethoxy) -1-chloroisoquinoline

The title compound was prepared from the hydrochloride

5-carboxymethoxy-1-chloroisoquinoline as a white powder. Melting point 163 to 166 ° C. 1 H (δ, DMSO-dg, 400 MHz) 4.6 (2H, s), 7.2 (1H, d), 7.45 (1 H, br s), 7.65 (1H, br s), 7.7 (1H, dd), 7.8 (1H, d), 8,25-8,2

(2H, m).

LRMS 237, 239 (MH &lt; + &gt;).

Found: C, 51.83; H, 4.13; N, 11.07. Calcd for C 1 H 8 ClN 4 + H ₂ O: C, 51.88; H, 4.35; N, 11.00.

Preparation 63

7-N-Benzylcarbamoyl-1-chloroisoquinoline

The title compound was prepared from 7-carboxy-1-chloroisoquinoline hydrochloride and benzylamine to give a tan solid.

• 4 4 4 • 4

44

Mp 144-145 ° C ^X H (δ, CDC1 _3, 400 MHz)? 4.7 (5H, m), 7.6 (1H, d), 7.85 (2H, d), 6.7 (1 H , br s), 7.45-7.25 (1 H, d), 8.15 (1 H, d), 8.3 (1 H,

d), 8.65 (1H, s).

LRMS 297 (MH), 593 (M ₂ H).

Preparation 64 1-Chloro-5-sulfamoylisoquinoline

To an ice-cooled solution of fuming sulfuric acid (20% SO ₃ , 2 mL) was added portionwise with stirring 1-chloroisoquinoline (1.0 g, 6.1 mmol). The mixture was stirred at room temperature for an additional 3 hours, then heated at 80 ° C for 18 hours, cooled in an ice bath and poured into ice (70 g), washed with ether and concentrated in vacuo. The residue was treated with isopropanol to give a white solid, which was filtered and dried to give 1-chloro-5-isoquinolinesulfonic acid (1.16 g, 4.77 mmol).

¹ H (δ, D ₂₀ , 400 MHz) 7.6 (1H, t), 8.10.84 (4H, m).

LRMS 244 (MH &lt; + &gt;).

1-Chloro-5-isoquinolinesulfonic acid suspension (1.14 g,

4.68 mmol) in thionyl chloride (13 mL) and DMF (0.3 mL, 3.9 mmol) was heated to reflux for 3 hours. Concentration in vacuo and azeotroping with toluene afforded 1-chloro-5-chlorosulfonylisoquinoline as an off-white solid which was used immediately.

A solution of 1-chloro-5-chlorosulfonylisoquinoline (613 mg, 2.34 mmol) in methylene chloride saturated with ammonia gas (20 mL) was stirred at room temperature for 18 hours, concentrated in vacuo to a white solid, and purified by silica gel column chromatography ( pre-absorbed) using EtOAc-hexanes (1: 1) as eluant to give 1-chloro-5-sulphamoylisoquinoline as a white solid (206

4 4 4 4 4 4

4444 • 44

4 »· 4,444

4 4

4 4

4 4 4 4

4 4

44

4 4 4

4 4 4

4 4 4 4

4 4 ·

(4 mg, 0.85 mmol).

Mp 216-218 ° C.

1 H (δ, DMSO-d 6, 400 MHz) 7.8 (1H, s), 7.9 (1H, t), 8.4 (1H, d), 8.45 (1H, S), 8.5 (1 H, d).

LRMS 243,245 (MH).

Found: C, 44.46; H, 3.01; N, 11.49. Calculated for C _g H ₇ ClN ₂ O ₂ S: C, 44.54; H, 2.91; N, 11.54.

Preparation 65

1-Chloro-7-sulfamoylisoquinoline

n-Butyllithium (0.35 mL, 2.5 M in hexanes, 0.875 mmol) was added dropwise under N ₂ and at -78 ° C to a stirred solution of 7-bromo-1-chloroisoquinoline (200 mg, 0.825 mmol) in tetrahydrofuran-ether (THF-Et ₂ O) (2.0 mL, 1: 1). After 5 minutes, the mixture was added under N ₂ and at -25 ° C to a solution of sulfuryl chloride (SO ₂ Cl ₂ ) (0.14 mL, 1.74 mmol) in hexane (2.0 mL) and the mixture was warmed to 23 ° C and stirred for 3 hours. Concentrated aqueous ammonia (3.0 mL, 0.880) was added and all solvent was evaporated in vacuo. The residue was suspended in EtOAc, washed with aqueous HCl (2 M), brine and then evaporated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (50:50 to 30:70) as eluant to give the title compound (37 mg, 0.152 mmol) as a white solid.

Mp 220-222 ° C.

Δ -H (CD ₃ OD, 400 MHz) δ 7.9 (1H, d), 8.2 (1H, d), 8.3 (1H, d), 8.4 (1H, d), 8, Δ (1H, s) ppm.

LRMS 243, 245 (MH ^&lt; ^{+ &gt;} ).

• · 99'- • · · · · · · · · · · · · · · · · · · · · * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *

- 80 Preparation 66 1-Chloro-7-phenylsulfamoylisoquinoline

n-Butllithium (0.88 mL, 2.5 M in hexanes, 2.2 mmol) was added dropwise under N ₂ and at -78 ° C to a stirred solution of 7-bromo-1-chloroisoquinoline (500 mg, 2, 06 mmol) in THF-ether (10 mL, 1: 1). After 5 min, the mixture was added at -25 ° C under N ₂ to a solution of SO ₂ Cl ₂ (0.35 mL, 4.36 mmol) in hexane (10 mL) and the mixture was warmed to 23 ° C and stirred for 4 min. 5 hours. The solvent was evaporated in vacuo, azeotroped with PhMe, the residue suspended in CH ₂ Cl ₂ (12 mL), and then aniline (0.25 mL, 2.74 mmol) and NEt ₃ (1.15 mL, 8 mL) were added. 25 mmol). The mixture was stirred at room temperature overnight, washed with aqueous HCl (2 M), brine and then evaporated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (80:20 to 50:50) as eluant to give the title compound (116 mg, 0.36 mmol) as an off-white solid.

^X H (CD ₃ OD, 400 MHz) δ 7.0-7.15 (3H, m), 7.2-7.25 (2H, m), 7.8 (1H, d), 8.1 ( 2H, 2xd), 8.4 (1H, d), 8.7 (1H, s) ppm.

LRMS 319, 321 (MH ^&lt; ^{+ &gt;} ).

Preparation 67

7-Chlorosulfonyl-1,4-dichloroisoquinoline (i)

-9 9- · - »• 9 9 • 9 9 9 • 9 9999

9 9

9

- 81 ····

9 9

9 9

9 9

9 9

9

9 9 9

9 9 «

9 9 «9 9 9

99

A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in acetonitrile (MeCN) (80 mL) was added to the stirred solution

Of 1- (2H) isoquinoline (10 g, 69 mmol) in MeCN (250 mL) which was heated to reflux. The mixture was heated at reflux for a further 1.5 hours and then cooled to room temperature. The resulting precipitate was collected by filtration, rinsed with MeCN and then dried in vacuo to give 4-chloro-1 (2H) -isoquinolone (11.3 g, 62.9 mmol) as a light pink solid.

¹ H (DMSO-d 6, 400 MHz) δ 7.5 (1H, s), 7.6 (1H, dd), 7.8-7.9 (2H, m), 8.25 (1H, d) 11.5 (1H br s), ppm LRMS 180, 182 (MH ^&lt; ^{+ &gt;} ), 359, 361, 363 (M2H ^& lt ^{; + &gt;} ).

(ii)

4-Chloro-1- (2H) -isoquinolinone (20.62 g, 115 mmol) was added dropwise at 0 ° C to a mixture of chlorosulfonic acid (61 mL,

918 mmol). The mixture was heated at 100 ° C for 3.5 days and then cooled to room temperature. The reaction mixture was added in small portions to a mixture of ice and water [CAUTION] and the resulting precipitate was collected by filtration. The solid was washed with water, triturated with MeCN and then dried in vacuo to yield a solid. φφ »

- 82 ·· φ φ φ φ φ φ φ> · · · ·

4-Chloro-7-chlorosulfonyl-1- (2H) -isoquinolone (18.75 g, 67.4 mmol) as a cream solid.

¹ H (DMSO-d₆, 400 MHz) δ 7.45 (1H, s), 7.8 (1H, d), 8.0 (1H, d), 8.5 (1H, s), 11.5 (1 H, br s) ppm.

Found: C, 39.37; H, 2.09; N, 4.94. Calcd for C ₉ H ₅ Cl ₂ NO ₃ S: C, 38.87; H, 1.81; N, 5.04.

(iii)

Phosphorus oxychloride (POCl ₃ ) (9.65 mL, 103.5 mmol) was added to a stirred suspension of 4-chloro-7-chlorosulfonyl-1- (2H) -isoquinolone (22.1 g, 79.6 mmol) at room temperature. ) in MeCN (500 mL) and the mixture was refluxed for 5 hours. Under cooling, the MeCN solution is decanted from the insoluble sludge and evaporated to dryness. The residue was extracted with EtOAc and evaporated to give a solid which was stirred with Et ₂ O (1.2 L) at room temperature overnight. The ether solution was decanted from the insoluble material and evaporated in vacuo to give 7-chlorosulfonyl-1,4-dichloroisoquinoline (20 g, 67 mmol) as a pale yellow solid.

¹ H (DMSO-d 6, 400 MHz) δ 8.2 (2H, S), 8.5 (1H, s), 8.55 (1H, s) ppm.

Found: C, 37.19; H, 1.34; N, 4.77. Calcd for C ₉ H ₄ Cl ₃ NO ₂ S: C, 36.45; H, 1.36; N, 4.72.

Preparation 68

1,4-Dichloro-7-sulfamoylisoquinoline • ·· ·

7-Chlorosulfonyl-1,4-dichloroisoquinoline (110 mg, 0.37 mmol) was dissolved in a solution of saturated methanolic ammonia (NH ₃ ) (10 mL) and the solution was stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo and the residue was azeotroped with CH ₂ C1 ₂ and then partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO ₄ ) and evaporated in vacuo to give 1,4-dichloro-7-sulfamoylisoquinoline (98 mg, 0.35 mmol) as a white solid.

1 H (DMSO-d 6, 400 MHz) δ 7.8 (2H, s), 8.35 (1H, d), 8.45 (1H, d), 8.6 (1H, s), 8.75 ( 1H, s) ppm.

LRMS 276, 278 (MH ^&lt; ^{+ &gt;} ).

Preparation 69

7-Cyclopentylsulfamoyl-1,4-dichloroisoquinoline

A mixture of cyclopentylamine (0.10 mL, 1.0 mmol), NEt ₃ (0.17 mL, 1.2 mmol) and 7-chlorosulfonyl-1,4-dichloroisoquinoline (250 mg, 0.84 mmol) in CH ₂ Cl ₂ (15 mL) was stirred at 23 ° C for 18 hours. The mixture was diluted with CH ₂ Cl ₂ (30 mL), washed with dilute HCl (2 Μ), saturated aqueous sodium bicarbonate (NaHCO ₃ ), brine, dried (MgSO ₄ ) and evaporated in vacuo to give a residue.

- 84 the title compound (250 mg, 0.72 mmol) as a white solid.

Melting point 165-167 ° C (decomposition).

¹ H (CDCl ₃ , 300 MHz) δ 1.3-1.95 (8H, m), 3.75 (1H, sextet),

4.6 (1H, d), 8.2 (1H, d), 8.2 (1H, d), 8.4 (1H, d), 8.5 (1H, d)

s), 8.9 (1H, s) ppm.

LRMS 346 (MH ^&lt; ^{+ &gt;} ).

Found: C, 48.76, H, 4.04; N, 7.98. Calcd for ^C 14 ^H 14 ^Cl 2 ^N 2 ° 2 ^{S: C} '48.71; H, 4.09; N, 8.11.

Preparation 70

1,4-Dichloro-7-pyrrolidinesulfonylisoquinoline

The title compound was prepared in the same general manner as Preparation 69.

Melting point 197-199 ° C.

^X H (CDC1 _3, 3, 00 MHz) δ 1.8 (4H, m), 3.4 (4H, m), 8.2 (1H, d), 8.4 (1H, d), 8.5 (1H, s), 8.8 (1H, s) ppm.

LRMS 331, 333 (MH ^&lt; ^{+ &gt;} ).

Found: C, 47.23; H, 3.60; N, 8.32. Calcd for ^C 13 ^H 12 ^Cl 2 ^N 2 ° 2 ^{S: C} ' ⁴⁷ '¹⁴; H, 3.65; N, 8.46.

Preparation 71

1,4-Dichloro-7-morpholinosulfonylisoquinoline · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The title compound was prepared in the same general manner as Preparation 69.

Melting point 170-171 ° C.

¹ H (CDCl ₃ , 400 MHz) δ 3.1 (4H, s), 3.8 (4H, s), 8.1 (1H, d), 8.4 (1H, s), 8.5 ( 1H, d), 8.8 (1H, s) ppm.

LRMS 348, 349 (MH ^&lt; ^{+ &gt;} ).

Found: C, 44.90; H, 3.43; N, 7.38. Calcd for ^C 13 ^H 12 ^Cl 2 ^N 2 ° 3 ^{S: C} ' ⁴⁴ '⁹⁷; ^H - 3.48; N, 8.07.

Preparation 72

1,4-Dichloro-7- (N-methylpiperazino) sulfonylisoquinoline hydrochloride

The title compound was prepared in the same general manner as Preparation 69.

Mp 260-261.5 ° C.

¹ H (CDCl ₃ , 400 MHz) δ 2.8 (3H, s), 3.1 (2H, br s), 3.5 (4H, br m), 4.0 (2H, brd), 8, 1 (1H, d), 8.4 (1H, d), 8.5 (1H, s),

8.8 (1H, s), 13.5 (1H, brs) ppm.

LRMS 360, 362 (MH ^&lt; ^{+ &gt;} ).

• ·

4 4 · 4 4 ··· 44 4 4445

4444 44 4 4 4 4 4 • 4 44 44 44 44 4 4 4 44 44 44 44

Found: C, 41.93; Η, 4.15; N, 10.08. Calculated for ^C 14 ^H 15 ^C1 2 ^N 3 ^S 2 ° - ^HC1 - o ^'4H 2 ^{0: C' 41/63} »· ^H, 4.19; N, 10.40.

Preparation 73

7-Bromo-4-chloro-1 (2H) -isoquinolone

A solution of N-chlorosuccinimide (4.13 g, 31 mmol) in MeCN (50 mL) was added dropwise to a stirred solution of 7-bromo-1- (2H) -isoquinolone (6.6 g, 29.5 mmol) in MeCN (150 mL), which was heated to reflux. The mixture was heated at reflux for an additional 3 hours and then cooled to room temperature. The resulting precipitate was collected by filtration, washed with MeCN and then dried in vacuo to give 7-bromo-4-chloro-1 (2H) -isoquinolone (6.72 g,

26.0 mmol) as a white solid.

Mp 241-243 ° C.

¹ H (DMSO-d₆, 300 MHz) 5 7.5 (1H, s), 7.73 (1H, d), 7.8 (1H, dd), 8.3 (1H, s) ppm.

LRMS 259 (MH ⁺ ), 517 (M ₂ H ⁺ ).

Found: C, 41.69; H, 1.90; N, 5.37. Calcd for C 8 H 9 BrClNO: C, 41.80; H, 1.95; N, 5.42.

Preparation 74

O

About ·· ···

NaH (45 mg, 80% dispersion in mineral oil, 1.5 mmol) was added under N ₂ and at 0 ° C to a stirred solution of 7-bromo-4-chloro-1- (2H) -isoquinolone (390 mg, 1 (5 mmol) in THF (15 mL) and the mixture was stirred for 5 to 10 minutes to give an orange solution. This solution was cooled to -78 ° C, a solution of n-BuLi (0.60 mL, 2.5 M in hexanes, 1.5 mmol) was added dropwise, and the solution was stirred for an additional 15 minutes. S-phenyl benzenethiosulfate (PhSO ₂ SPh) (378 mg, 1.5 mmol) in THF (5 mL) was added, the solution was stirred at -70 ° C for 10 minutes and then allowed to warm slowly to room temperature. Water (30 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water, brine, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by silica gel column chromatography using CH ₂ Cl ₂ -MeOH-0.880 NH ₃ (95: 5: 0.5) as eluant, then recrystallized from EtOAc to give 4-chloro-7- (phenylsulfanyl). -1-1 (2H) -isoquinolone (186 mg, 0.64 mmol) as a white solid. A second portion of the material (40 mg, 0.14 mmol) was obtained from the mother liquors.

¹ H (DMSO-d 6, 300 MHz) δ 7.35-7.5 (6H, m), 7.7 (1H, d), 7.8 (1H, d), 8.0 (1H, s) ppm.

LRMS 288, 290 (MH ^&lt; ^{+ &gt;} ), 575 (M &lt; _{2 &gt;} H ^&lt; ^{+ &gt;} ).

Found: C, 61.85; H, 3.48; N, 4.81. Calcd for ^C 15 ^H 10 ^ClN 5 ^O 2 S, ^25H 2 ^O: C, 61.64; H, 3.62; N, 4.79.

Preparation 75

1,4-Dichloro-7- (phenylsulfanyl) isoquinoline

O

Cl «toto · · toto toto · · · ·

POCl 3 (46 μΐ, 0.50 mmol) was added to a stirred suspension of 4-chloro-7- (phenylsulfanyl) -1- (2H) -isoquinolone (120 mg, 0.42 mmol) in MeCN (2 mL) at 23 ° C. The mixture was heated at reflux for 1.5 h to give a clear solution. This cold solution was poured into water (20 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (90:10) as eluant to give 1,4-dichloro-7- (phenylsulfanyl) isoquinoline (92 mg, 0.30 mmol) as an oil which solidified on standing . .

¹ H (CDCl ₃ , 300 MHz) δ 7.45 (3H, m), 7.55 (2H, m), 7.65 (1H, dd), 8.1 (1H, d), 8.1 ( 1H, s), 8.3 (1H, s) ppm.

LRMS 306, 308 (MH ^&lt; ^{+ &gt;} ).

Found: C, 57.90; H, 2.99; N, 4.67. Calculated for C ₁₅ H _g Cl ₂ NS.0,25H ₂ O: C, 57.98; H, 3.08; N, 4.51.

Preparation 76

1,4-Dichloro-7- (phenylsulfonyl) isoquinoline

mCPBa (270 mg, 50-55 wt%, 0.78 mmol) was added at 23 ° C to a stirred solution of 1,4-dichloro-7- (phenylsulfanyl) isoquinoline (120 mg, 0.39 mmol) in CH ₂ Cl ₂ (20 mL) and stirred for 4 h. The solution was washed with aqueous NaHCO ₃ (3x, 10%), brine, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by silica gel column chromatography using hexanes-EtOAc (70:30) as eluant, followed by crystallization with CH ₂ Cl ₂ -i-Pr ₂ O to give 1,4-dichloro-7- (phenylsulfonyl) isoquinoline ( 87 g, 0.25 mmol) as a white solid.

¹ H (CDCl ₃ , 300 MHz) δ 7.5-7.7 (3H, m), 8.05 (2H, d), 8.15

Claims (32)

PATENT CLAIMS 1-guanidino-7-phenylsulfamoylisoquinoline; 1-guanidino-7-sulfamoylisoquinoline; 1-hydroxycyclohexyl, 1-hydroxycyclopentyl, COPh, CH (OH) CH ₃ , CH (OH) Ph, CCH ₃ (OH) Ph, OCH ₂ Ph, SO ₂ Ph, SPh, CH ₂ OPh, SO ₂ NH ₂ , SO ₂ NHPh, SO ₂ NH (cyclopentyl), SO ₂ (pyrrolidino), S0 ₂ (morpholino), S0 ₂ (N-methylpiperazirto) (2-methylimidazol-1-yl) methyl, (2-methylbenzimidazole-1-yl) methyl, benzofuran-2-yl, thien-3-yl, thieno 2-yl, 4-methylpentyl, 1,3-benzo [d] dioxol-5-yl, CN, _CH2 OH, CONHBn, 4-methoxyphenyl, A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein one of R ¹ and R ² is hydrogen and the other is N = C (NH ₂ ) ₂ or NHC (= NH) NH ₂ , R ³ is H, halogen, Ο _1-6 alkyl optionally substituted by one or more halogen atoms or C ₃ _G alkoxy optionally substituted by one or more halogen atoms, R ⁴ , R ⁵ , R ⁸ and R ⁷ are each independently H, OH, halogen, C 1-6 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen or OH, C 1-6 alkoxy, optionally substituted with one or more halogens, CN, CO (C 1-6 alkyl, optionally substituted with one or more halogens), (C 1-4 alkylene) CO 2 R ⁸ , (C 11 alkylene) CN, 0 (C _n -alkylene) CN, 0 (C _n -alkylene) CO ₂ R ⁸ , (C m-alkylene) CONR ⁹ R ¹⁰ (C m-alkylene) NR ⁹ COR ¹⁰ , 0 (C _n -alkylene) CONR ⁹ R ^10, (C _m - alkylene) NR ⁹ SO 2 R ^11, (C m - alkylene) S (O) p R ^11, (C _m - alkylene) SO ₂ NR ⁹ R ^10, CH = CHCOR ^8, CH = CHCONR ⁹ R ^10, CH = CHSO ₂ R ⁸ , CH = CHSO ² NR ⁹ R ¹⁰ , CH = CHSO 2 aryl, or a group of formula X-aryl or X-het, or wherein two of R ⁴ , R ⁵ , R ⁸ and R ⁷ are bonded to adjacent atoms carbon and may together form a moiety -O (C 11 -alkylene) O-, R ⁸ is H, C 1-4 alkyl, optionally substituted with one or more - 91 halogens, or aryl (C ₁ _G alkylene) R ⁹ and R ¹⁰ are each independently Η, C ^ g alkyl, optionally substituted by one or more halogen, aryl (C ₁ _G alkylene), aryl, heteroaryl or heteroaryl (C j__g alyklen), or ^R9 and R10 may be taken together with an alkylene moiety to form, with the atoms to which they are attached, a 4- to 7-membered ring, optionally containing another hetero group selected from O or S or NR ¹² , R ¹¹ is aryl, heteroaryl or C 1-6 alkyl, optionally substituted with one or more halo, R ¹² is H, C ₁ _ ₆ alkyl optionally substituted with one or more halogen, or CO (C | __g alkyl, optionally substituted with one or more halogens) X is a direct bond, C _n - alkylene, 0 (C _n - alkylene) 0 0 (C _n -alkylene), CH (OH), C (C ₁ _ ₆ alkyl) 0H, CO, S (O) _p ( C _m - alkylene), (C _m - alkylene) S (0) CH = CH or C≡C, aryl is phenyl or naphthyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen or OH, C alkoxy, optionally substituted with one or more halogens, CN, O (C _n -alkylene) CN, (C _n) - alkylene) CN, CO (C -] __ g alkyl, optionally substituted with one or more halogens), (C _m - alkylene) CO ₂ R ^13, O (C _n - alkylene) CO ₂ R ^13, (C _m - alkylene) C0NR ¹⁴ R ^15, (C _m - alkylene) NR ¹⁴ COR ^15, 0 (C _n - alkylene) C0NR ¹⁴ R ^15, (C _m - alkylene) S ( 0) ^R13, (Cm - alkylene) SO 2 NR ¹⁴ R ^15, - alkylene) NR ¹⁴ SO 2 R @ ⁶ CH = CHSO2R ¹³ CH CHSO2NR ¹⁴ R ^15, CH = CHSO2aryl ^1, CH = CHCOR ^13, and CH = CHCONR ¹⁴ R ¹⁵ , (C, heteroaryl is an optionally benzocondensed 5- or 6-membered heterocyclic group bonded by any suitable atom in the heterocycle or benzene ring (if present), wherein: · · · · · · The heterocyclic group is selected from the group consisting of dioxolyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrazinyl and pyranyl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, optionally substituted with one or more halogens, or OH, O _1-6 alkoxy, optionally substituted with one or more halogens , CN, O ( _Cn - alkylene) CN, (C _n - alkylene) CN, COÍC- ^ g alkyl, optionally substituted with one or more halogens), (C _m alkylene) CO ₂ R ¹³ , O (C ¹¹ - alkylene) CO ₂ R ¹³ , (Cm - CONR ¹⁴ R ¹⁵ , (C 1-4 alkylene) NR ¹⁴ COR ^15.0 (Cn - alkylene) CONR ¹⁴ R ^15, (cm alkylene) NR ¹⁴ SO 2 R ^16, (C _m - alkylene) S (O) pR ¹³ , (C 1-4 alkylene) SO ² NR ¹⁴ R ¹⁵ , CH = CHCOR ¹³ , CH = CHCONR ¹⁴ R ¹⁵ , CH = CHSO ² R ¹³ , CH = CHSO ² NR ¹⁴ R ¹⁵ , CH = CHSO ² aryl, het is optionally a benzofused 5- or 6-membered heterocyclic group bonded to Part X by any suitable atom in the heterocycle or benzene ring (if present), wherein the heterocyclic group is selected from the group consisting of dioxolyl, dioxolanyl, furyl, thienyl, pyrrolyl, oxazolyl, oxazinyl, thiazinyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl or their fully saturated, partially or fully saturated analogs wherein said het is or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, optionally substituted with one or more halogens and OH, alkoxy, optionally substituted with one or more halogens, CN, O (C _11-18) - alkylene) CN, (C _n - alkylene) CN, CO (C ₁ _G alkyl, optionally substituted with one or more halogens), (C _m - alkylene) CO ₂ R ^13, 0 (C n - alkylene) CO 2 R ^13, (Cm • • · · · · · · · · • - §3 CONR ¹⁴ R ¹⁵ , (C 1-4 alkylene) NR ¹⁴ COR ^15.0 (Cn - alkylene) CONR ¹⁴ R ^15, (cm alkylene) NR ¹⁴ SO 2 R ^16, (C _m - alkylene) S (O) p R ¹³ , (C 1-4 alkylene) SO ² NR ¹⁴ R ¹⁵ , CH = CHCOR ¹³ , CH = CHCONR ¹⁴ R ¹⁵ , CH = CHSO ² R ¹³ , CH = CHSO ² NR ¹⁴ R ¹⁵ and CH = CHSO ² aryl, aryl ¹ is phenyl or naphthyl, optionally substituted with one or more substituents independently selected from halogen, alkyl, optionally substituted with one or more substituents independently selected from halogen or OH, C 1-6 alkoxy, optionally substituted with one or more halogens, CN, O (C _n -alkylene) CN, (C _n -alkylene) CN, 00 (O _1-6 alkyl, optionally substituted with one or more halogens), (C _m - alkylene) CO ₂ R ^13, 0 (C n - alkylene) CO 2 R ^13, (C m - alkylene) CONR ¹⁴ R ¹⁵ (C m - alkylene) NR ¹⁴ COR ^15, 0 (C n - alkylene) CONR ¹⁴ R ^15, (C _m alkylene) S (O) R ¹³ , (C 1-4 alkylene) SO ² NR ¹⁴ R ¹⁵ , (Cr - alkylene) NR ¹⁴ SO 2 R ^16, CH = CHSO2R ^13, CH = CHSO ₂ NR ¹⁴ R ^15, CH = CHCOR ¹³ and CH = CHCONR ¹⁴ R ¹⁵ , m R ¹³ is H, C - ^ - g alkyl, optionally substituted by one or more halogen, or aryl ² (C ₁ _G alkylene) R ¹⁴ and R ¹⁸ are each independently selected from the group consisting of hydrogen, C ^ g alkyl, optionally substituted with halogen, aryl ² (C ₁ _G alkylene), aryl ^2, heteroaryl ¹ or heteroaryl ¹ (C -] __ g alkylene) or R ⁹ and R ¹⁰ may be bonded together with the alkylene moiety to form, with the atoms to which they are attached, a 4- to 7-membered ring, optionally containing an additional hetero group selected from O or S or NR ¹² , R ¹⁸ is aryl ^2, heteroaryl ¹ or C ₁ _G alkyl, optionally substituted with one or more halogen, aryl ² is phenyl or naphthyl, optionally substituted by one or more substituents independently selected from the group comprising halogen, C ₁ _G alkyl optionally substituted with one or more substituents independently selected from halo or OH; - 94 C- ^ g alkoxy, optionally substituted by one or more halogen, CN, 0 (C _n - alkylene) CN, (C _n - alkylene) CN, or CO (C ₁ _G alkyl optionally substituted with one or more halogen), heteroaryl ¹ is an optionally fused 5- or 6-membered heterocyclic group bonded by any suitable atom in the heterocycle or benzene ring (if present), wherein the heterocyclic group is selected from dioxolyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C -j__g alkyl, optionally substituted with one or more substituents independently selected from halogen or OH, C _L _ ₆ alkoxy, optionally substituted with one or more ha Logen, CN, 0 (C _n - alkylene) CN, (C _n - alkylene) CN, or CO (C ₁ _G alkyl optionally substituted with one or more halogen), wherein the C-alkylene binding groups mentioned in the definitions above are linear or branched and are optionally substituted with one or more (C 1-6 alkyl groups optionally substituted with one or more halogens) groups, m is an integer from 0 to 3, n is an integer from 1 to 3, and p is an integer from 0 to 2. 2+ PNH NHP. (IV) where P and P-1 are N-protecting groups, despite the formation of a compound of formula (v) or a salt thereof: (IN) 2,6-dimethoxyphenyl, 3-carboxyphenyl, 3-cyanophenyl or 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, The compound or salt of claim 1, wherein R ¹ is N = C (NH ₂ ) ₂ or NHC (= NH) NH ₂ and R ² is H. • • • · · 3-methoxyphenyl. 3-chlorophenyl. 4 4 4 4 4 4 «and subsequent deprotection. 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 · 4444 « -.ďoi: 44 4444 44 ·· 4 4 4 4 4 · 4 4-chloro-1-guanidino-7- (phenylsulfonyl) isoquinoline; and salts thereof. 4-chloro-1-guanidino-7- (phenylsulfanyl) isoquinoline; 4-chloro-7-cyclopentylsulfamoyl-1-guanidinoisoquinoline; 4-chloro-1-guanidino-7- (1-pyrrolidinosulfonyl) isoquinoline hydrochloride; 4-chloro-1-guanidino-7 - [(N-methylpiperazino) sulfonyl] isoquinoline 4-chloro-1-guanidino-7-morpholinesulfonylisoquinoline hydrochloride; 4-chloro-1-guanidino-7-phenylsulfamoylisoquinoline; (4-chloro-7- (α-hydroxybenzyl) isoquinolin-1-yl) guanidine; (4-chloro-7- (3-carboxyphenyl) isoquinolin-1-yl) guanidine; (4-bromo-7- (4-methoxyphenyl) isoquinolin-1-yl) guanidine; (4-chloro-7- (2,6-dimethoxyphenyl) isoquinolin-1-yl) guanidine; (4-bromo-7- (3-methoxyphenyl) isoquinolin-1-yl) guanidine; (4-chloro-7- (4-methoxyphenyl) isoquinolin-1-yl) guanidine; (4-chloro-7- (3-methoxyphenyl) isoquinolin-1-yl) guanidine; (4-chloro-7- (2-methoxyphenyl) isoquinolin-1-yl) guanidine; 4-methoxyphenyl, 2,6-dimethoxyphenyl, SO ₂ NH ₂ , SO ₂ NHPh, SO ₂ NH (cyclopentyl), SO ₂ (pyrrolidino), SO ₂ (morpholino), SO ₂ Ph, SPh, SO ₂ (N-methylpiperazino) or 3-carboxyphenyl. · 9 4. A compound or salt according to any preceding claim, wherein R ⁴ is H, OH, halo, C-j__g alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen or OH, C ₁ _G alkoxy, optionally substituted one or more halogen, CN, _(Cm -alkylene) CONR @ R @ ^1, O (Cn-alkylene) CONR R ^18, (Cm -alkylene) SO ₂ NR ⁹ R ¹⁰ or a group of formula X-aryl or X-het. 5. A compound or salt according to any preceding claim wherein R ⁵ is H, halogen or C ₁ _G alkyl, optionally substituted with one or more substituents independently selected from halogen or OH. The compound or salt of claim 1 or 2, wherein R ³ is H, halogen or alkyl, optionally substituted with one or more halogen atoms. A compound or salt according to any preceding claim, wherein R ⁶ is H, halogen, C 1-8 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen or OH, C 1-8 alkoxy, optionally substituted with one or more more halogens, CN, O (C _n -alkylene) CN, (C _n -alkylene) CN, (C _m -alkylene) CONR 4 R ¹⁰ , (C _m -alkylene) CO 2 R ⁸ , (C m-alkylene) SO ₂ NR ⁹ R ^10, (C _m - alkylene) S (0) p R ¹¹ or a group of formula X-aryl or X-het. A compound or salt according to any preceding claim, wherein R ⁷ is H. A compound or salt according to any one of the preceding claims, wherein R ³ is H, halogen or C _1-4 alkyl, optionally substituted with one or more halogen atoms. ' • 9 • 9 - · 100 · 9 9 9 9 9 9 9 9 9 - * 58 - ....... 9 ····· · · · 9 9 9 99 · 9 9 9 9 9 9 9 9 9 · 9 9 9 9 9 9 9 9 · 9 · 999 · - * 97 and where the phenyl moiety linked via X is optionally substituted with one or more halogen, C ₁ _ _g alkyl optionally substituted by one or more substituents independently selected from halogen and OH, C ₁ _ _g alkoxy, optionally substituted by one or more halogen or CO ₂ R ^18, wherein Het ¹ is optionally benzo-fused dioxolyl, furyl, thienyl, imidazolyl, or a partially or fully saturated analogues, and wherein such het ¹ group bonded via X is optionally substituted with one or more C ₁ _ _g alkyl groups, optionally substituted with one or more substituents independently selected from halogen and OH. 9. A compound or salt according to any preceding claim, wherein R ⁴ is H, Br, OH, CN, C j__g alkoxy, C ₁ _G alkyl, optionally substituted by one or more OH, SO ₂ NR ⁹ R ^10, CONR ⁹ R ^10, R ¹⁰ OCH2CONR ^9, OCH2aryl, Het or aryl. A compound or salt according to any preceding claim, wherein R ⁵ is H, Br or methyl, optionally substituted with one or more halogen atoms. 11. A compound or salt according to any preceding claim, wherein R ⁶ is H, Cl, Br, C ^ -g alkyl, optionally substituted with one or more substituents selected from the group consisting of OH, C ₁ _G alkoxy, CN, (C _m - alkylene) CONR ⁹ R ^10, (C m - alkylene) CO 2 R ^8, (Cm - alkylene) S (O) p R ¹¹ (C ₁ - alkylene) SO ₂ NR ⁹ R ¹ ® or a group of formula X-aryl or X-het, where X is a direct bond, CH = CH, CH (OH), CO, OCH ₂ , CH ₂ O or CH ₂ . The compound or salt of any one of the preceding claims, wherein R ³ is H, Cl, Br or methyl. 13. A compound or salt according to any preceding claim, wherein R ⁴ is H, Br, OH, CN, C j__g alkoxy, C ₁ _G alkyl, optionally substituted by one or more OH, SO ₂ NR ⁹ R ¹ ®. CONH (aryl (C _1-6 alkyl)), CONH ₂ , OCH ₂ CONR ⁹ R ¹⁰ , OCH ₂ aryl, phenyl or naphthyl. A compound or salt according to any preceding claim, wherein R ⁵ is H, Br or methyl. The compound or salt of any one of the preceding claims, wherein R ⁸ is H, Br, methyl, optionally substituted OH, ethyl optionally substituted by OH, cyclopentyl optionally substituted by OH, cyclohexyl optionally substituted with OH, alkoxy, CN, O (C _n - alkylene) CN, (C _n - alkylene) CN, SO ₂ R ^{1 L,} SR ¹¹ , CONR ⁹ R ¹⁰ , CO ² R ⁸ , SO ² NR ⁹ R ¹⁰ , a group of formula X- (optionally substituted phenyl) or X-het ¹ , wherein X is a direct bond, CH = CH, CH (OH), CO, OCH ₂ , CH ₂ O or CH ₂ , A compound or salt according to any preceding claim, wherein R ⁴ is H, Br, CN, OCH ₃ , SO ₂ NH ₂ , CH ₂ OH, CONH ₂ , OCH ₂ CONH ₂ , CONHBn, OH or Ph. A compound or salt according to any preceding claim, wherein R ⁶ is H, Br, CO ₂ H, (E) CH = CHPh, Ph, OCH ₃ , A compound or salt according to any one of the preceding claims, wherein R ⁶ is CH (OH) Ph, 2-methoxyphenyl, 3-methoxyphenyl, A compound or salt according to any one of the preceding claims, wherein R ¹ is N = C (NH ₂ ) ₂ or NH (C (= NH) NH ₂ , each of R ² , R ⁴ , R ⁵ and R ⁷ are H, R ³ is Br or Cl and R ⁶ is 2-methoxyphenyl, 4-methoxyphenyl, CH (OH) Ph, SO ₂ Ph, SPh, 3-carboxyphenyl or The compound or salt of claim 1, wherein two of R ⁴ , R ⁴ , R 8 and R ⁷ are bonded to adjacent carbon atoms and together form part of OCH ₂ O. The compound or salt of claim 1, substantially as described in the examples of the present invention. The compound or salt of claim 1, which is: 23. Pharmaceutical composition characterized in that the 99 ·· · • ^Λ • a • · · · · · · • * «• · · · · in that it comprises a compound or salt according to any preceding claim in admixture with a compatible adjuvant, diluent or carrier . A compound or salt according to any one of claims 1 to 22 for use as a medicament. Use of a compound or salt as defined in any one of claims 1 to 22 for the preparation of a medicament for the treatment of conditions or procedures mediated by uPA. Use according to claim 25, wherein the condition or process is selected from the group consisting of chronic skin ulcer, angiogenesis (neovascularization), bone remodeling, implantation of an embryo into the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue conversion during healing wound and organ differentiation, fibrosis, local invasion of tumors into adjacent areas, metastatic development of tumor cells from primary sites to secondary sites, and tissue destruction in arthritis. A method of treating a condition or process mediated by uPA, comprising administering an effective amount of a compound or salt of any one of claims 1 to 22, or a composition as defined in claim 23. The method of claim 27, wherein the condition or process is selected from chronic skin ulcer, angiogenesis, bone remodeling, implantation of the embryo into the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue conversion during healing wound and organ differentiation, fibrosis, local invasion of tumors into adjacent areas, metastatic development of tumor cells from primary sites to secondary sites, and tissue destruction in arthritis. A process for preparing a compound or salt according to claim 1, comprising reacting a 1- or 3-aminoisoquinoline derivative II, wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in claim 1: with cyanamide (NH ₂ CN) or another reagent that acts as NHC ⁺ = NH synthon. A process for the preparation of a compound or salt according to claim 1, comprising reacting a 1-or 3-aminoisoquinoline derivative II as defined in claim 29 with an agent which acts as a protected amidine (2+) synton IV: A process for preparing a compound of formula (I) according to claim 1 or a salt thereof, comprising reacting a compound of formula (VI) wherein R ³ , R ⁴ , R ⁵ , R 6 and R ⁷ are as defined in claim 1 and wherein: is attached at the 1- or 3-position and is a leaving group in which the leaving group is replaced with the free base of guanidine. A compound of formula v as defined in claim 30