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President Barack Obama has said the US is prepared to work with any nation, including Russia and Iran, to resolve the conflict in Syria.
He told the UN General Assembly in New York compromise would be essential for ending the long civil war.
But he said realism required a “managed transition” away from Syria’s President Bashar al-Assad to an inclusive leader.
He and Russian President Vladimir Putin, who is a key ally of Syria, are to hold rare talks later.
The assembly in New York is expected to see intense diplomatic activity on the conflict, which has claimed more than 200,000 lives and forced four million to flee abroad.
In his remarks, Mr Obama called President Assad a “tyrant” who dropped barrel bombs on children.
“Lasting stability can only take hold when the people of Syria forge an agreement to live together peacefully,” he said.
“The US is prepared to work with any nation, including Russia and Iran, to resolve the conflict. But we must recognise that there cannot be, after so much bloodshed, so much carnage, a return to the pre-war status quo.”
The summit is due to hear from Mr Putin shortly, as well as Iranian President Hassan Rouhani and French President Francois Hollande, whose country has just carried out its first air strikes against Islamic State (IS) militants in Syria.
Putin centre stage, by BBC’s Steve Rosenberg in Moscow
A famous Russian expression talks about “killing two hares with one shot”. But Vladimir Putin doesn’t do things by halves: he’ll be trying to slay a whole multitude of political and economic hares with one trip to New York.
His UN speech and meeting with President Obama will put President Putin centre stage: a return to the international limelight for a leader shunned by the West over the conflict in Ukraine.
Mr Putin told US TV that the Syrian president’s forces were the only legitimate conventional army in Syria
And if he convinces President Obama to put aside their differences and join together in the fight against Islamic State, Russia stands to gain on many levels: by retaining a degree of influence in Syria; by boosting Russian national security (Moscow acknowledges that IS constitutes a threat to Russia); and, crucially, by improving Russia’s international image – rebranding her from pariah to partner and refocusing attention from the conflict in Ukraine.
If Vladimir Putin achieves that, it could be the first step towards easing Western sanctions.
First, though, he will need to convince the US to trust him. It may be a hard sell.
In his speech, UN Secretary General Ban Ki-moon said five countries – Russia, the US, Saudi Arabia, Turkey and Iran – were key to finding a political solution, but unless they could compromise it would be “futile” to expect change on the ground.
Moscow has suggested there are plans to form an international contact group involving all the countries Mr Ban mentioned plus Egypt.
The threat of IS extremists and the flow of Syrian refugees to Europe has added urgency to the search for a deal to end the civil war.
Western leaders have recently softened their stance towards the Syrian president, conceding that he might be able to stay on during a political transition.
Mr Putin, who has strongly reinforced Russia’s military presence in Syria, has called for a regional “co-ordinating structure” against IS, and said the Syrian president’s troops were “the only legitimate conventional army there”.
He said Russia would not participate in any troop operations in Syria.
President Rouhani – a key regional ally of President Assad – says the government in Damascus “can’t be weakened” if IS militants are to be defeated.
Why the UN General Assembly matters
Syria’s civil war
What’s the human cost?
More than 250,000 Syrians have been killed and one million injured in four and a half years of armed conflict, which began with anti-government protests before escalating into a full-scale civil war.
And the survivors?
More than 11 million others have been forced from their homes, four million of them abroad, as forces loyal to President Assad and those opposed to his rule battle each other – as well as jihadist militants from IS. Growing numbers of refugees are going to Europe.
How has the world reacted?
Regional and world powers have also been drawn into the conflict. Iran and Russia, along with Lebanon’s Hezbollah movement, are propping up the Alawite-led government. Turkey, Saudi Arabia and Qatar are backing the Sunni-dominated opposition, along with the US, UK and France.
Diplomatic goals behind Putin’s Syria build-up
Migrant crisis: Fleeing life under Islamic State in Syria
The battle for Syria and Iraq in maps
UK Prime Minister David Cameron is expected to reflect the softening of the Western stance against Mr Assad this week.
He is set to tell leaders at the gathering in New York that Mr Assad could remain temporarily in power at the head of a transitional government.
In addition to Russia’s military build-up in Syria, Iraq on Sunday announced that it had signed an agreement on security and intelligence co-operation with Russia, Iran and Syria to help combat IS.
A US-led coalition has been carrying out air strikes against IS in Syria and Iraq for more than a year.
The UK announced this month it had carried out a drone strike against two British citizens in Syria, but has yet to fly manned operations in Syrian airspace.
BBC